Methods for treating depression in patients via renal neuromodulation

ABSTRACT

Methods for treating depression and for reducing a risk associated with developing depression in patients via therapeutic renal neuromodulation and associated systems are disclosed herein. Sympathetic nerve activity can contribute to several cellular and physiological conditions associated with depression as well as an increased risk of developing depression. One aspect of the present technology is directed to methods for improving a patient&#39;s calculated risk score corresponding to a depression status in the patient. Other aspects are directed to reducing a likelihood of developing depression in patients presenting one or more depression risk factors. Renal sympathetic nerve activity can be attenuated to improve a patient&#39;s depression status or risk of developing depression. The attenuation can be achieved, for example, using an intravascularly positioned catheter carrying a therapeutic assembly configured to use, e.g., electrically-induced, thermally-induced, and/or chemically-induced approaches to modulate the renal sympathetic nerve.

CROSS-REFERENCE TO RELATED APPLICATION(S)

The present application claims priority to U.S. Provisional PatentApplication No. 62/528,876, filed Jul. 5, 2017, and to U.S. ProvisionalPatent Application No. 62/570,603, filed Oct. 10, 2017, both of whichare incorporated herein by reference in their entireties.

TECHNICAL FIELD

The present technology relates generally to systems, devices, andmethods for treating depression and/or for reducing a risk associatedwith developing depression in patients via renal neuromodulation.

BACKGROUND

Depression is a mental condition that is characterized by persistentfeelings of sadness and/or worthlessness, as well as lack of desire toengage in activities that were previously enjoyable. Depending onseverity of depression-rated symptoms, number of symptoms and/orpersistence (e.g., duration) of symptoms, depression can interfere withmental and/or social function in the affected person, greatly impactingquality of life. In the most severe cases, depression can lead tosuicide. The World Health Organization estimates that more than 300million people of all ages suffer from depression and close to 800,000people die due to suicide every year. Depression can affect a person atany age or time, with women being twice as likely as men to experiencedepression in their lifetime.

Depression is typically treated with a combination of medication (e.g.,antidepressants) and psychotherapy. Despite current treatment options,however, the burden of depression and other related mental healthconditions is on the rise globally. For example, the World HealthOrganization predicts that depression will rank second to heart diseaseby the year 2020, and will be the leading cause of disease burden by2030. As depression can have severe psychological, cognitive, physical,social and economic impact on patients as well as families and society,there is a need for treatments that effectively treat and/or managedepression, including the severity of symptoms associated withdepression. Furthermore, there is a need for treatments that effectivelyreduce the incidence of depression, or provide other improvements inprognosis and outcomes for patients having depression or at risk ofdeveloping depression.

BRIEF DESCRIPTION OF THE DRAWINGS

Many aspects of the present disclosure can be better understood withreference to the following drawings. The components in the drawings arenot necessarily to scale. Instead, emphasis is placed on illustratingclearly the principles of the present disclosure.

FIG. 1 is a conceptual illustration of the sympathetic nervous system(SNS) and how the brain communicates with the body via the SNS.

FIG. 2 is a conceptual illustration of the peripheral and brainrenin-angiotensin-systems in the human body.

FIG. 3 is an enlarged anatomic view of nerves of a left kidney to formthe renal plexus surrounding the left renal artery.

FIG. 4 illustrates an intravascular neuromodulation system configured inaccordance with an embodiment of the present technology.

FIGS. 5A and 5B are anatomic views of the arterial vasculature andvenous vasculature, respectively, of a human.

FIG. 6 illustrates modulating renal nerves with a neuromodulation systemconfigured in accordance with an embodiment of the present technology.

FIG. 7 is a block diagram illustrating a method of modulating renalnerves in accordance with an embodiment of the present technology.

FIG. 8 is a block diagram illustrating a method for improving adepression risk score for a patient in accordance with an embodiment ofthe present technology.

FIG. 9A is a display table illustrating results from a study todetermine the effects of renal denervation on cortical axon density andmean norepinephrine concentration in animal subjects.

FIG. 9B is a series of graphs illustrating the response correlationbetween normalized cortical axon area vs. norepinephrine concentrationand norepinephrine concentration vs. extent of nerve ablation along theartery of the animal subjects of FIG. 9A.

FIG. 10 illustrates a depression risk score calculator for determining apatient's depression risk score in accordance with an embodiment of thepresent technology.

DETAILED DESCRIPTION

The present technology is directed to methods for treating depression,managing symptoms or sequelae associated with depression, reducing aseverity of depression, and/or for reducing a risk associated withdeveloping depression in patients via renal neuromodulation. In certainembodiments, the present technology is directed to beneficiallyimproving one or more measurable physiological parameters associatedwith depression in a patient via renal neuromodulation. Otherembodiments of the present technology include performingtherapeutically-effective renal neuromodulation on a patient to reduce aseverity of neurobiological symptoms relating to depression. Furtherembodiments of the present technology include performingtherapeutically-effective renal neuromodulation on a patient to reducethe risk of occurrence of depression in at-risk patients. In yet anotherembodiment, a patient having had one or more previous episodes ofdepression can be treated with therapeutically-effective renalneuromodulation to reduce a risk associated with reoccurrence ofdepression or a depressive episode.

In a particular embodiment, for example, the patient has experienced oneor more severe or debilitating episodes of depression that pose ameasurable risk of experiencing a reoccurrence of another severe and/ordebilitating depressive episode, but the patient does not currently meetthe standard for a depression diagnosis. In some embodiments, thepatient exhibits one or more additional risk factors for the developmentof depression following a traumatic event, life change or stressfulsituation. Other embodiments of the present technology includeperforming therapeutically-effective renal neuromodulation on a patientprior to the patient experiencing a potentially life-threateningdepressive episode. For example, the patient may be a new mother at riskof severe postpartum depression or, in another embodiment, the patientmay have had one or more suicide attempts during previous depressiveepisodes.

The present technology is further directed to methods for reducing anincidence of cardiovascular disease or a cardiovascular event indepressed patients or patients diagnosed with clinical depression. Incertain embodiments, for example, the present technology is directed toimproving one or more measurable physiological parameters associatedwith cardiovascular health in the patient experiencing depression viarenal neuromodulation. Other embodiments of the present technologyinclude performing therapeutically-effective renal neuromodulation on apatient diagnosed with depression to reduce a severity of acardiovascular condition. Further embodiments of the present technologyinclude performing therapeutically-effective renal neuromodulation on apatient diagnosed with depression to reduce the risk of occurrence of acardiovascular event in such patient in later life.

As discussed in greater detail below, therapeutically-effective renalneuromodulation can include rendering neural fibers inert, inactive, orotherwise completely or partially reduced in function. This result canbe electrically-induced, thermally-induced, or induced by anothermechanism during a renal neuromodulation procedure, e.g., a procedureincluding percutaneous transluminal intravascular access.

Specific details of several embodiments of the technology are describedbelow with reference to FIGS. 1-10. The embodiments can include, forexample, modulating nerves proximate (e.g., at or near) a renal artery,a renal vein, and/or other suitable structures. Although many of theembodiments are described herein with respect to electrically-induced,thermally-induced, and chemically-induced approaches, other treatmentmodalities in addition to those described herein are within the scope ofthe present technology. Additionally, other embodiments of the presenttechnology can have different configurations, components, or proceduresthan those described herein. A person of ordinary skill in the art,therefore, will accordingly understand that the technology can haveother embodiments with additional elements and that the technology canhave other embodiments without several of the features shown anddescribed below with reference to FIGS. 1-10.

As used herein, the terms “distal” and “proximal” define a position ordirection with respect to the treating clinician or clinician's controldevice (e.g., a handle assembly). “Distal” or “distally” can refer to aposition distant from or in a direction away from the clinician orclinician's control device. “Proximal” and “proximally” can refer to aposition near or in a direction toward the clinician or clinician'scontrol device.

I. DEPRESSION

Depressive disorders are characterized by feelings of sadness that aresevere and/or persistent enough to interfere with function and are oftenaccompanied by decreased interest or pleasure in activities previouslyenjoyed by the patient. Persons with mild, moderate or severe depressivesymptoms report difficulties with work, home and/or social activities,and numerous studies have also shown that persons with depression havemore functional limitations than those without depression.

As used herein, “depression” refers to any form of depressive disorderor illness associated with feelings of despondency and/or dejectionexperienced by an individual and persisting for at least two weeks,and/or in which one or more depression screening tools or instrumentsare used to give a professionally-accepted diagnosis.

There are several forms of depressive disorders that are distinguishedby a spectrum of symptom types and severity as well as the persistenceof the disorder in an affected individual. For a clinically-accepteddiagnosis of depression, the American Psychiatric Association definesthe criteria in its Diagnostic and Statistical Manual of MentalDisorders (DSM-5). Identifiable and clinical symptoms of depression mayinclude a depressed mood for most of the day, diminished interest orpleasure in all or almost all activities, insomnia or hypersomnia,psychomotor agitation or retardation nearly every day, fatigue or lossof energy, poor appetite or overeating, low self-esteem or feelings ofworthlessness, changes in cognitive ability, negative feelings aboutself or the world, and/or thoughts of suicide. In all forms ofdepression, however, affected and/or susceptible individuals may developongoing (chronic), short-term (acute) or recurring depression withpotential for debilitating mental and physical health outcomes.

The two most common forms of depression include major depressivedisorder (MDD) and persistent depressive disorder (PDD). MDD is adisorder in which the combination of symptoms are so severe as to bedisabling, and a major depressive episode can commonly occur severaltimes in a person's lifetime. MDD (e.g., unipolar disorder) typicallycauses grave interferences with the individual's ability to work, sleep,eat and/or enjoy any activity. Patients may appear miserable and showlimited physical and/or emotional connection with the world around them.For diagnosis of a MDD episode, five or more depression-related symptomsmust be present nearly every day during the same two week period withone of the symptoms being either depressed mood or anhedonia (e.g., lossof interest or pleasure in previously enjoyable activities) (DSM-5).

PDD is manifest by the presence of symptoms for at least 2 years withoutremission. In some cases, symptoms may begin during adolescence andpersist into adulthood, sometimes lasting for many years or decades. Thenumber of symptoms may fluctuate above and below the threshold for MDD,and must include at least two of the following: poor appetite orovereating, insomnia or hypersomnia, anergia (e.g., low energy orfatigue), low self-esteem, poor concentration or difficulty makingdecisions, and feelings of hopelessness.

Each of MDD and PDD can present with additional specifiers or extensionsto the disorder in a particular patient that form the basis forvariations of depression in individuals. For example, an MDD episode orPDD may present with anxious distress (e.g., fear or worry), asmelancholic (e.g., lost pleasure in nearly all activities and areparticularly despondent and despairing), as atypical (e.g., moodtemporarily brightens in response to positive events but may exhibitoverreaction to criticism/rejection, increased appetite, hypersomnia andfeelings of heaviness in the extremities), as psychotic (e.g., episodesincluding break with reality, hallucinations, delusions, etc.), ascatatonic (e.g., having severe psychomotor retardation), with seasonalor cyclic patterns (e.g., seasonal affective disorder (SAD) which ischaracterized by the onset of a depressive illness during the wintermonths), and with peripartum onset (e.g., depressive episode occurringduring pregnancy or in the four weeks following delivery; psychoticfeatures may be present). Another form of depression in women includespremenstrual dysphoric disorder (PMDD) which cycles with menstruationand typically occurs in the week before menstruation begins. Anadditional mood disorder that includes depressive episodes is bipolardisorder. Bipolar disorder is characterized by cycling mood changesbetween highs (e.g., mania or hypomania) and lows (e.g., depression)that may meet the DSM-5 criteria for major depression.

Vascular depression, sometimes occurring in the elderly, results whenblood vessels become constricted due to less flexibility and hardening.Depression-like symptoms typically present when normal blood flow to thebody's organs, including the brain, is restricted or lowered. Additionalcauses of depression or depression-like symptoms may accompany or be dueto diseases or illnesses such as, for example, thyroid disorders,adrenal gland disorders, benign or malignant brain tumors, stroke,cardiovascular disease, acquired immune deficiency syndrome (AIDS),Parkinson's disease, and multiple sclerosis. Certain pharmaceuticaldrugs (e.g., corticosteroids, some beta-blockers, interferon, reserpine,etc.), or abuse of certain recreational drugs (e.g., alcohol,amphetamines) can cause or accompany depression.

The etiology and symptoms associated with a depressive disorder aredistinguishable from low or discouraged moods that may result fromdisappointments/demoralization (e.g., financial difficulties or losses,natural disaster, illness, relationship problems) and losses (e.g.,death of a loved one). The negative feelings associated withdemoralization and grief tend to occur in waves when the individual isreminded of the triggering event, and tend to resolve when circumstancesimprove for the individual. While a low mood can last for days, weeks oreven months, prolonged loss of function, suicidal thoughts and feelingsof worthlessness are not likely.

As discussed above, diagnosis of depression is based on theidentification of the clinical criteria (e.g., symptoms and signs) asset forth in DSM-5. Clinicians and other mental health practitionerstypically use conventionally accepted diagnostic test methods, such asscreening tools (e.g., for use during diagnostic interviews, patienthealth questionnaires, etc.) for identifying depression risk, severityand diagnosis. These screening tools are typically focused on coredepression symptoms as set forth in DSM-5, but some screening toolsprovide further diagnostic capability to determine symptom severity,various specifiers, and/or other risk factors (Serra, F., et al., Front.Psychol, 2017, 8, 214; Bech, P., et al., BMC Psychiatry, 2015, 15:190).For example, severity is typically determined by the degree ofdisability (e.g., cognitive, physical, social, occupational, etc.) orpain experienced by the patient as well as the duration of the symptoms.These screening tools are also designed to differentiate depressivedisorders from demoralization and grief as well as other mentaldisorders (e.g., anxiety disorders). For example, patients can bediagnosed with depression and/or a measure of depression severity can bedetermined using the Major Depression Inventory (MDI), Patient HealthQuestionnaire (PHQ-9), the Mini-International Neuropsychiatric Interview(MINI), the Hamilton Depression Scale (HAM-D17), the Bech-RafaelsenMelancholia Scale (MES), the Zung Self-rating Depression Scale(Zung-SDS), the Beck Depression Inventory-II (BDI-II), and/or a VisualAnalogue Scale for Depression Severity (VAS), among others, as is knownin the art (Id.). Many of these screening tools provide a risk score forpredicting depression status with respect to diagnosis, depressionseverity and/or identifying at-risk populations (Id.). Other screeninginstruments, such as the Formal Psychological Assessment (FPA), look atmultiple risk and symptom factors beyond the conventional screeningtools to provide a patient's clinical state that includes a generaldepression factor as well as weighted symptom profiles for cognitive,somatic and affective sub-factors that can be taken into account whenproposing treatments and/or measuring improvements in the patientfollowing treatment (Serra, F., et al., Front. Psychol, 2017, 8, 214).

Certain risk factors have been identified that may make an individualmore likely (e.g., increase a risk) to develop depression during theirlifetime. For example, some identified risk factors for increasing alikelihood of developing depression include having a family historyand/or personal history of depression or other mental illness,experiencing adverse life events (e.g., illness, abuse, loss of a lovedone, unemployment, psychological trauma, etc.), having experienced priortraumatic events, being a childhood survivor of abuse, experiencingtrauma during childhood, having a history of substance abuse,experiencing a difficult relationship, being in a stressful situation,experiencing a major life change, experiencing an extended period ofstress (e.g., chronic stress), low level of education, unmarried,smoker, physically inactive and female gender among others (World HealthOrganization; Raison, C. L. and Miller, A. H., Cerebrum, 2013, August:1-16; Anda, R. et al., Epidemiology, 1993, 4: 285-294).

Patients with depression may also experience other adverse mental andphysical diseases and disorders. For example, depression has highcomorbidity with mental disorders such as anxiety disorders, substanceand alcohol abuse, and panic disorder (Hirschfeld, R. M. A, J ClinPsychiatry, 2001, 3: 244-254). Further, cardiovascular disease, stroke,hypertension, obesity (e.g., high body mass index (BMI)), cancer,Parkinson's disease, and metabolic disorders, such as type 2 diabetes,among others are also highly comorbid with depression (Halaris, A., CurrTopics Behav Neurosci, 2017, 31:45-70; Brown, A. D., et al., CNS Drugs,2009, 23:583-602; Anda, R. et al., Epidemiology, 1993, 4: 285-294; Dhar,A. K. and Barton, D. A., Front. Psychiatry, 2016, 7:33; Jangpangi, D.,et al., J Clin Diagn Res, 2016, 10:4-6; Everson-Rose, S. A., et al.,Stroke, 2014, 45: 2318-2323; National Institute of Mental Health).Without being bound by theory, it is possible that depression sharesunderlying neuroendocrine, metabolic and other psychophysiologicalpatterns with these other disorders that either increase risk fordepression development or reduce treatment success and/or increase riskfor the development of these additional conditions.

A. Biophysical Characteristics of Individuals with Depression

Depression is a mood disorder category encompassing complex andmultifactorial disorders that are thought to be caused by manycontributing factors. The underlying neurobiological and metabolicmechanisms or etiology of depression are uncertain; however, evidencesuggests that psychological, genomic and other biological risk factorsare present in patients identified with depression. Moreover,neurobiological heterogeneity in monoaminergic transmitter systems, thehypothalamic-pituitary-adrenal (HPA) axis, metabolic hormonal pathways,inflammatory mechanisms, and psychophysiological reactive and neuralcircuits have been demonstrated between individuals diagnosed withdepression and healthy individuals (Spijker, A. T. and van Rossum, E. F.C., Neuroendocrinology, 2012, 95:179-186; Liu, F., et al., Int J PhysiolPathophysiol Pharmacol, 2012, 4: 28-35; Halaris, A., Curr Topics BehavNeurosci, 2017, 31:45-70; Raison, C. L. and Miller, A. H., Cerebrum,2013; Jedema, H. P. and Grace, A. A., J Neurosci, 2004, 24:9703-9713;Everson-Rose, S. A., et al., Stroke, 2014, 45: 2318-2323). In additionto differences between individuals diagnosed with depression and healthyindividuals, those who do meet the criteria for depression can vary inthe severity of their symptoms as well as the type of symptoms theyexperience.

Psychological stress, including chronic stress, can have deleteriouseffects on the brain's neural circuits as well as whole-bodyphysiological states, and is a crucial factor underlying depression,with variation in stress susceptibility, responsivity and resilienceproviding variances in disorder presentation and severity (Halaris, A.,Curr Topics Behav Neurosci, 2017, 31:45-70). The neuro-hormonal systemsthat play a critical role in stress responses and homeostasis includethe HPA axis and noradrenergic systems. The noradrenergic systemincludes a dense network of axons that extend from the locus coeruleusin the brain stem throughout the brain including the hippocampus,amygdala, thalamus and hypothalamus, as well as projections that extenddown the brain stem to synapse with sympathetic nerve fibers in thethoracic region.

Correlative links have been established between depression and chronicor prolonged hyperactivity of the sympathetic branch of the autonomicnervous system (Dhar, A. K. and Barton, D. A., Front. Psychiatry, 2016,7:33; Halaris, A., Curr Topics Behav Neurosci, 2017, 31:45-70; Miller,A. H., et al., Biol Psychiatry, 2009, 65: 732-741). As shown in FIG. 1,the SNS is a branch of the autonomic nervous system along with theenteric nervous system and parasympathetic nervous system. The SNS isprimarily an involuntary bodily control system typically associated withstress responses. It is always active at a basal level (calledsympathetic tone) and becomes more active during times of stress. Fibersof the SNS extend through tissue in almost every organ system of thehuman body. For example, some fibers extend from the brain, intertwinealong the aorta, and branch out to various organs. As groups of fibersapproach specific organs, fibers particular to the organs can separatefrom the groups. The SNS regulates the function of virtually all humanorgan systems by localized release of catecholamines (e.g.,norepinephrine) from sympathetic nerve terminals innervating thesetissue and organ systems, spillover of norepinephrine from vascularneuro-muscular junctions (the primary source of norepinephrine inplasma), and by systemic circulation of catecholamines (e.g.,epinephrine, norepinephrine) released from the adrenal gland in responseto acute, transient stress or threats. Long-term variations in basallevels, increases in basal levels due to aging, as well as spikes ofcirculating catecholamines from hyperactivity of the SNS responding tolife circumstances can also exert more enduring regulatory effects ongene expression by altering constitutive gene expression profiles in awide variety of tissues and organ systems.

Once released, norepinephrine binds adrenergic receptors on peripheraltissues. In addition, activation (e.g., norepinephrine release) ofnoradrenergic nuclei in the central nervous system (CNS) can result fromtransmitted impulses from activated afferent renal sympathetic neurons.Binding to adrenergic receptors either in the periphery or in the CNScauses a neuronal and hormonal response. The physiologic manifestationsinclude pupil dilation, increased heart rate, occasional vomiting, andincreased blood pressure. Increased sweating is also seen due to bindingof cholinergic receptors of the sweat glands. It is known that long-termSNS hyperactivity has been identified as a major contributor to thecomplex pathophysiology of hypertension, states of volume overload (suchas heart failure), and progressive renal disease, both experimentallyand in humans. Moreover, correlative links between activation of the SNSand systemic inflammation, arterial stiffness, atherosclerosis,metabolic disorders, insulin resistance, and other cardiovascularconditions have been established. As mentioned above, many of theseconditions are comorbid with depression.

Increased SNS tone with demonstrated increased levels of catecholamine(e.g., norepinephrine) spillover and secretion are associated withdepression diagnosis. For example, increased levels of catecholamines(e.g., norepinephrine) and their metabolites (e.g., vanillylmandelicacid) excreted in urine have been documented in patients diagnosed withdepression (e.g., MDD) (Sherin, J. E., et al., Dialogues Clin Neurosci,2011, 13: 263-278). Further, higher levels of circulatingcatecholamines, such as norepinephrine (in the periphery and centralnervous systems), have been reported in mood disorders includingdepression; and an activated noradrenergic system is implicated inpsychological stress, which is one of the primary risk factors fordepression development (Dhar, A. K. and Barton, D. A., Front.Psychiatry, 2016, 7:33; Miller, A. H., et al., Biol Psychiatry, 2009,65: 732-741; Halaris, A., Curr Topics Behav Neurosci, 2017, 31:45-70).The elevated plasma levels of norepinephrine as well as excreted urinelevels of norepinephrine originate from an increase in the steady-stateextravascular norepinephrine appearance rate as well as an increase inthe rate of norepinephrine appearance in plasma and not from differencesin clearance rates between depressed and non-depressed individuals(Dhar, A. K. and Barton, D. A., Front. Psychiatry, 2016, 7:33; Sherin,J. E., et al., Dialogues Clin Neurosci, 2011, 13: 263-278). Thissuggests that increased SNS activity is present in depressed patients.

Other indicators of increased SNS tone in patients with depressioninclude elevations in heart rate, blood pressure, and plateletactivation as well as a decrease in heart rate variability (e.g., ameasure of beat-to-beat fluctuations in heart rate) (Halaris, A., CurrTopics Behav Neurosci, 2017, 31:45-70; Jangpangi, D., et al., J ClinDiagn Res, 2016, 10:4-6; Dhar, A. K. and Barton, D. A., Front.Psychiatry, 2016, 7:33; Alvares, G. A., et al., J Psychiatry Neurosci,2016, 41: 89-104). In contrast, healthy individuals that do not meet thecriteria for depression may exhibit significantly lower plasmacatecholamine levels and may not display other indicators of elevatedSNS activity (Sherin, J. E., et al., Dialogues Clin Neurosci, 2011, 13:263-278; Alvares, G. A., et al., J Psychiatry Neurosci, 2016, 41:89-104).

Without being bound by theory, increased levels of norepinephrine canaccount for many aspects of depression-associated symptoms, includingincreased negative emotions, sleep disturbances (e.g., insomnia),impaired concentration, self-isolation, and suicidal ideation (Miller,A. H., et al., Biol Psychiatry, 2009, 65: 732-741; Sah, R. andGeracioti, T. D., Mol Psychiatry, 2013, 18:646-655). Hyperactive SNSactivity in patients with depression also presents an on-going challengeto treatment success as levels of norepinephrine increase or spike inresponse to stressors and/or worsening psychological stress in theseindividuals (Miller, A. H., et al., Biol Psychiatry, 2009, 65: 732-741;Dhar, A. K. and Barton, D. A., Front. Psychiatry, 2016, 7:33; Alvares,G. A., et al., J Psychiatry Neurosci, 2016, 41: 89-104).

Depression and other mood disorders have also been linked to elevatednorepinephrine release in the brain and further central sympatheticoutflow to the periphery via the brain renin-angiotensin system (RAS)(Liu, F., et al., Int J Physiol Pathophysiol Pharmacol, 2012, 4: 28-35).FIG. 2 is a conceptual illustration of the peripheral and brainrenin-angiotensin-systems in the human body. Specifically, angiotensinII, which is widely expressed in the brain and plays roles in bloodpressure regulation, functions via its receptor, AT₁R, to increase bloodpressure and activate the SNS (Tsuda, K., Int J Hypertens, 2012, ArticleID 474870, 1-11; Liu, F., et al., Int J Physiol Pathophysiol Pharmacol,2012, 4: 28-35). However, continuous activation of brain RAS viapolymorphisms in the angiotensin I-converting-enzyme (ACE) gene or theAT₁R gene (which are highly associated with depression), for example,lead to oxidative stress in the brain, SNS hyperactivity, and inhibitionof baroreflex, and is further associated with impaired cognitivefunction and heightened emotional stress responses (Liu, F., et al., IntJ Physiol Pathophysiol Pharmacol, 2012, 4: 28-35). Renal sympatheticactivity, which can be activated by spillover of central sympatheticoutflow via renal efferent nerve fibers, causes the kidneys to increaseperipheral renin production, which ultimately leads to increasedangiotensin II production via the peripheral RAS (Oparil, S. andSchmieder, R. E., Circ Res, 2015, 116:1074-1095). Renin, which is anangiotensinogenase, is secreted by the afferent arterioles of the kidneyfrom specialized cells of the juxtaglomerular apparatus, and in responseto SNS activity as well as decreases in arterial blood pressure orsodium levels (Id.). Renin primarily activates other components of theperipheral RAS which ultimately results in an increase in peripheralangiotensin II, which is responsible for several systemic alterationsincluding increasing sympathetic activity, increases in blood pressureand increases in aldosterone production and release from the adrenalcortex (Id.).

Peripheral circulating angiotensin II, via activation of peripheral RAS,cannot pass the blood-brain barrier (BBB); however it is linked toactivation of brain RAS via angiotensin II receptors oncircumventricular organs of the brain (Liu, F., et al., Int J PhysiolPathophysiol Pharmacol, 2012, 4: 28-35). Without being bound by theory,elevated renin production via renal sympathetic activity is correlatedwith activation of brain RAS which further promotes sympatheticactivity. These central and peripheral neural regulation components areconsiderably stimulated in depression, which is characterized byheightened sympathetic tone, and likely contributes to other diseasestates, such as hypertension and cardiovascular disease, among others.

Individuals with depression also exhibit altered HPA axis function asevidenced by elevated levels of corticotropin-releasing hormone (CRH),which initiates stimulation of the HPA axis in response to stress (e.g.,psychological stress, etc.) (Bissette, G., et al.,Neuropsychopharmacology, 2003, 28: 1328-1335). Hyperactivity of the HPAaxis as well as higher circulating cortisol (i.e., glucocorticoid)levels compared to healthy controls (e.g., patients with no history ofdepression) also exemplify HPA axis dysfunction in remitted as well ascurrently depressed patients (Spijker, A. T. and van Rossum, E. F. C.,Neuroendocrinology, 2012, 95:179-186). Decreased responsiveness toglucocorticoids (e.g., glucocorticoid resistance) and subsequent HPAaxis dysfunction is a hallmark of major depression (Miller, A. H., etal., Biol Psychiatry, 2009, 65: 732-741). Alterations to HPA axisfunction, both reflecting a current mood state as well as long lastingchanges to brain function, may be mediated, in part, by alterations inthe glucocorticoid receptor. In particular, it has been demonstratedthat patients with depression exhibit reduced glucocorticoidsensitivity, preferential expression of a dominate negative form (GR-β)of the glucocorticoid receptor, and increased levels of FKBP5, which isa co-chaperone of the glucocorticoid receptor that inhibits ligandbinding and pathway activation (Menke, A., et al., Genes, Brain andBehav, 2013, 12: 289-296; Spijker, A. T. and van Rossum, E. F. C.,Neuroendocrinology, 2012, 95:179-186; Miller, A. H., et al., BiolPsychiatry, 2009, 65: 732-741). An individual's level of chronicexposure to stress, and thereby cortisol exposure, in brain regionsassociated with emotion and cognition (e.g., the limbic system), arebelieved to be important in the development or prediction of future riskof depression in the individual, and this additional major stressresponse system may determine longer-term patterns of stress responsesin depressed patients (Spijker, A. T. and van Rossum, E. F. C.,Neuroendocrinology, 2012, 95:179-186).

CRH and norepinephrine are known to interact in regions of the braininvolved in stress responses to interfere in emotional response,cognition and encoding of emotional memories (Jedema, H. P. and Grace,A. A., J Neurosci, 2004, 24:9703-9713). Further reinforcing a prolongedpsychological stress response and the pathophysiology of depression, CRHis elevated in the locus coeruleus of depressed patients and has beenshown to activate neurons in the locus coeruleus resulting in increasednorepinephrine levels throughout the CNS (Jedema, H. P. and Grace, A.A., J Neurosci, 2004, 24:9703-9713; Bissette, G., et al.,Neuropsychopharmacology, 2003, 28: 1328-1335).

Neuropeptide Y (NPY), a 36-amino-acid peptide transmitter that isexpressed in brain regions that regulate stress and emotional behaviors,has shown to buffer stress responses and promote increased ability tocope with emotional trauma (Enman, N. M., et al., Neurobiol Stress,2015, 1: 33-43; Sah, R. and Geracioti, T. D., Mol Psychiatry, 2013,18:646-655). In particular, central nervous system NPY concentrationlevels may normally control or suppress pro-stress transmitters such asCRH and norepinephrine in the brain (Id.). However, both central andperipheral nervous system NPY concentrations are significantly lower inindividuals with depression when compared to healthy controls (Id.),possibly attenuating the individuals' resilience and coping ability inresponse to psychological stress. Without being bound by theory, andsince NPY functions to inhibit CRH and norepinephrine promotion ofstress and fear responses, as well as reduces the release ofnorepinephrine from sympathetic neurons, decreased NPY activity maycontribute to SNS hyperactivity in patients with depression (Enman, N.M., et al., Neurobiol Stress, 2015, 1: 33-43).

An additional physiological characteristic associated with depressionincludes a pro-inflammatory state, including chronic inflammation(Raison, C. L. and Miller, A. H., Cerebrum, 2013; Miller, A. H., et al.,Biol Psychiatry, 2009, 65: 732-741; Halaris, A., Curr Topics BehavNeurosci, 2017, 31:45-70). For example, elevated levels of inflammatorycytokines, such as interleukin-6 (IL-6), IL-1β, IL-2, and tumor necrosisfactor-alpha (TNF-α) as well as other inflammatory markers, such asC-reactive protein (CRP), are elevated in individuals with depression,and peripheral levels of these inflammatory markers correlate positivelywith depression symptomology (e.g., fatigue, cognitive dysfunction,impaired sleep) (Id.). Moreover, higher levels of inflammatorybiomarkers are associated with exacerbated depression symptoms as wellas an increased risk in the development of depression (Halaris, A., CurrTopics Behav Neurosci, 2017, 31:45-70). Psychological stress andresultant noradrenergic response mounts an immune response in the bodywhich also contributes to immunological alterations to the vascularendothelium leading to endothelium dysfunction, a trait marker fordepression (Halaris, A., Curr Topics Behav Neurosci, 2017, 31:45-70).

Depression is also associated with increased activation of thetranscriptional factor, nuclear factor-κB (NF-κB), which is activated byexposure to psychosocial stress and sympathetic nervous system outflowpathways, and is responsible for cytokine production (Miller, A. H., etal., Biol Psychiatry, 2009, 65: 732-741). Cytokine-induced increases inneural activity in brain regions, such as the anterior cingulated cortexand the basal ganglia, have been associated the development of mood andanxiety symptoms, and are associated with alterations in brainneurotransmitter metabolism (e.g., serotonin, norepinephrine anddopamine), neuroendocrine function and neural plasticity (Raison, C. L.and Miller, A. H., Cerebrum, 2013; Miller, A. H., et al., BiolPsychiatry, 2009, 65: 732-741). For example, cytokine-induced immuneresponses have shown to increase the number of reuptake pumps, therebydecreasing neurotransmitter availability, and shunting tryptophan awayfrom the production of serotonin in the brain (Raison, C. L. and Miller,A. H., Cerebrum, 2013; Halaris, A., Curr Topics Behav Neurosci, 2017,31:45-70). Without being bound by theory, increased SNS activity coupledwith reduced sensitivity to the anti-inflammatory effects ofglucocorticoids (e.g., due to glucocorticoid resistance) as a result ofchronic psychological stress, both contribute to chronic activation ofinflammatory responses.

In addition to biochemical heterogeneity between those individuals withdepression and healthy individuals (e.g., with no previous depressiveepisode), neuroanatomical differences have also been shown. For example,reduced hippocampal volume (e.g., left hippocampal atrophy), possiblyacquired via stress-induced inhibition of neurogenesis and/orneurotoxicity within the hippocampus, is particular associated withdepression and memory deficits associated with both symptomatic andremitted depression (Bearden, C. E., et al., ASN Neuro, 2009,1(4):art:e00020.doi:10.1042/AN20090026; Sapolsky, R. M., PNAS, 2001, 98:12320-12322). In particular, differences in hippocampal volume are foundin patients having had depression for greater than 2 years and/or whohad more than a single depressive episode, suggesting that hippocampalvolume reduction typically occurs after the on-set of depression in thepatient and does not appear to be a predisposing risk factor for thedevelopment of depression (Id.).

Currently prescribed treatment plans for patients diagnosed withdepression typically consist of pharmaceutical drugs and/orpsychotherapy. Conventional drug therapies are administered to addressparticular symptoms associated with depression in attempts to lessenthose particular symptoms. For example, antidepressants (e.g., selectiveserotonin reuptake inhibitors (SSRIs) that raise the level of serotoninin the brain, tricyclic antidepressants, monoamine oxidase inhibitors(MAOIs), etc.), anti-anxiety medication (e.g., benzodiazepines,buspirone, β-blocker, etc.), anti-psychotic drugs, anti-hypertensivedrugs, mood stabilizers, etc., may provide mild to moderate and/ortemporary relief from depression-related symptoms, sleep disturbances,cognitive and/or memory difficulties, etc. However, most patients do notget adequate treatment (e.g., up to 70% of patients) and for manypatients (e.g., up to 40%), antidepressants are ineffective. Moreover,drug adherence over several years or decades in a manner than maintainsmood, depression-related symptoms, sleep quality, blood pressure, etc.,remains a challenge for most patients. For many patients, improvementsmay not be apparent until after up to 4 or more weeks of drug treatment,causing delays in ascertaining whether the prescribed drug or drugcombination is suitable for the particular patient. Furthermore, somemedications do not work or stop working effectively over time.Additional drawbacks to use of drugs for treating a patient withdepression include the possibilities of adverse reactions associatedwith these medications (e.g., heart failure, hypotension, bradycardia,severe depressive episodes, suicide ideation, insomnia, sexualdysfunction, weight gain or unhealthy weight loss, death, etc.), as wellas other undesirable side-effects, on a patient-by-patient basis. Somestudies suggest that antidepressant drugs further reduce heart ratevariability in patients which can exacerbate depression severity orpredispose patients to future depressive episodes (Halaris, A., CurrTopics Behav Neurosci, 2017, 31:45-70). Additionally, pharmaceuticalintervention for other contributors and risk factors associated withdepression further complicates drug administration and management ofcontraindications between anti-inflammatory medications,anti-hypertensive drugs, antidepressant drugs, anti-anxiety drugs, moodstabilizers among others administered to support patients withdepression, and adherence over years remains a challenge. Variouspsychotherapy treatments can be prescribed in combination with amedication plan or as a stand-alone treatment. While psychotherapy(e.g., cognitive-behavioral therapy, interpersonal therapy, etc.) mayprovide some patients with skills in new ways of thinking and behaving,it may not be effective for more severe forms of depression such as MDD.Some patients with severe or medication adverse and/or resistantdepression may be treated with several sessions of electroconvulsivetherapy, phototherapy, deep brain stimulation and others with mixedresults. Various aspects of the present technology address SNS effectson risk factors associated with depression while overcoming thesechallenges.

B. Risk Factors Associated with Development of Depression and/or RelatedConditions

As discussed above, depression is a psychophysiological disorderencompassing dysregulation of complex neuro- and hormonal-biochemicalpathways that are known to be caused by many contributing factors. Whilemany biomarkers distinguishing patients with depression and healthyindividuals demonstrate heterogeneity following depression pathogenesisin an individual, certain earlier-identifiable conditions as well asgenetic and/or biophysical variances in a patient are recognized asbeing either contributory factors and/or predictors of a likelihood thata patient will develop depression or, in the case of remitted patients,a likelihood that the patient will have another depressive episode. Inparticular, many underlying conditions, genetic variances and otherabnormalities detectable in individuals either prior to the developmentof depression or during depression remittance, may affect the likelihoodof the individual subsequently developing depression/having a depressiveepisode. Such underlying conditions and genetic/biophysical variancesconstitute depression predictors or risk factors.

As discussed above, some identified risk factors for increasing alikelihood of developing depression include certain demographicvariables such as, for example, female gender, being unmarried (e.g.,single, divorced or widowed), low level of education, smoker, beingphysically inactive, among others (World Health Organization; Raison, C.L. and Miller, A. H., Cerebrum, 2013, August: 1-16; Anda, R. et al.,Epidemiology, 1993, 4: 285-294). Additionally, it has been shown that ifthe patient has a history of mental illness or substance abuse, has afamily history of depression or other mental illness, has experiencedone or more adverse life events (e.g., illness, abuse, loss of a lovedone, unemployment, psychological trauma, etc.), has or is experiencing adifficult relationship, has experienced prior traumatic events, has hadan adverse childhood experience, is currently in a stressful situation,has or is experiencing a major life change, or has or is experiencing anextended period of stress (e.g., chronic stress), among others, thepatient has an increased likelihood of developing depression (Id.).

Without being bound by theory, increased SNS activity in the patient asa result of psychological and/or other forms of chronic stress canpredispose the individual to developing depression. For example, chronicstress has been shown to alter neural circuits and structures in thebrain (e.g., hippocampus, prefrontal cortex, etc.) that may increase theindividual's sensitivity to contextual threat (Pitman, R. K., et al.,Nat Rev Neurosci., 2012, 13: 769-787). Moreover, lower heart ratevariability characterizes depression and may also be predictive ofdepression development (Jangpangi, D., et al., J Clin Diagn Res, 2016,10:4-6). In certain embodiments, prior exposure to trauma (e.g.,childhood abuse, prior sexual abuse, prior combat experience, etc.) mayincrease the individual's sensitization of the SNS, thereby lowering thethreshold barriers for the development of a depressive disorder.

While there is evidence for the presence of SNS hyperactivity inpatients with depression, there is further evidence that a strongadrenergic response to a traumatic event or other adverse lifecircumstance may mediate or in part contribute to the development ofdepression in certain individuals. Some biochemical inducements of theincrease in norepinephrine release in response to SNS activation includegenetic and/or other inhibition paths that lower NPY levels, as well aslower numbers or affinity of α2-adrenergic receptors (Pitman, R. K., etal., Nat Rev Neurosci., 2012, 13: 769-787). Additionally, there isevidence that a pro-inflammatory state (e.g., as indicated by increasedlevels of inflammatory cytokines) may increase risk or vulnerability fordevelopment of depression particularly when patients present withchronic stress (Halaris, A., Curr Topics Behav Neurosci, 2017,31:45-70). For example, it has been shown that increased levels of CRP(e.g., greater than about 3 mg/L; greater than about 5 mg/L; etc.) werepredictive of psychological distress and depression, and elevated levelsof CRP can present as an additional risk factor that can establish apredictive risk for the development of depression (Halaris, A., CurrTopics Behav Neurosci, 2017, 31:45-70; Raison, C. L. and Miller, A. H.,Cerebrum, 2013, August: 1-16; Miller, A. H., et al., Biol Psychiatry,2009, 65: 732-741).

Correlative links between activation of the SNS and high blood pressure,coronary heart disease, stroke, systemic inflammation, arterialstiffness, endothelium dysfunction, atherosclerosis, metabolicdisorders, insulin resistance, end organ damage, obesity (e.g., highbody mass index (BMI)), and other cardiovascular conditions have alsobeen established. As discussed above, these conditions/diseases havefurther been shown to be correlative with an incidence of depression(Halaris, A., Curr Topics Behav Neurosci, 2017, 31:45-70; Brown, A. D.,et al., CNS Drugs, 2009, 23:583-602; Anda, R. et al., Epidemiology,1993, 4: 285-294; Dhar, A. K. and Barton, D. A., Front. Psychiatry,2016, 7:33; Jangpangi, D., et al., J Clin Diagn Res, 2016, 10:4-6;Everson-Rose, S. A., et al., Stroke, 2014, 45: 2318-2323; NationalInstitute of Mental Health). As such, it is posited that theseconditions/diseases, which are indicative of chronic activation of SNS,present as risk factors that can establish a predictive risk for thedevelopment of depression. In fact, depression is more prevalent inpeople who have suffered a major cardiac event, with up to 40% of thesepatients developing depression (Dhar, A. K. and Barton, D. A., Front.Psychiatry, 2016, 7:33). Other studies have suggested even higher rates:74% of patients following a myocardial infarction (MI), 50% of patientshaving coronary artery bypass surgery, and 65% of women having suffereda major cardiac event (Id.). Strokes (e.g., acute ischemic stroke,lacunar stroke, transient ischemic attack (TIA), hemorrhagic stroke,etc.) are also highly associated with the development of depression withup to one third of stroke patients developing depression, andpost-stroke depression is associated with increased morbidity andmortality in such patients (Towfighi, A., et al., Stroke, 2017, 48:e30-e43).

Additionally, with respect to blood pressure regulation, the nocturnalblood pressure of healthy individuals drops or “dips” more than 10% ofthe average daytime blood pressure value, which is followed by anincrease in blood pressure with arousal from sleep, known as the morningsurge in blood pressure (MSBP). In contrast, “elevated,” i.e. limiteddrops in blood pressure during the nighttime (e.g., nighttime bloodpressure reduction that is less than 10% of average daytime bloodpressure) as well as excessive surge in MSBP (e.g., early morninghours), is associated with an increased risk of cardiovascular eventsand strokes even in normotensive patients (FitzGerald, L., et al., J HumHypertens, 2012, 26: 228-235). Depression correlates with higher MSBPand the increase in MSBP is proportional to the severity of depressionsymptoms and is irrespective of “dipping” status (Id.). Men and olderpopulations of patients further demonstrate “non-dipping” nocturnalblood pressure which is further associated with more depression symptomsand poorer overall sleep quality as well as increased risk incardiovascular events (Id.). Psychological risk factors, such asdepression and anxiety, are reported to influence cardiovascular eventsand to impact hypertension, and excessive MSBP and/or “non-dipping”nocturnal blood pressure may be risk factors for the development and/orthe severity for hypertension, cardiovascular disease and stroke.Moreover, excessive MSBP and/or “non-dipping” nocturnal blood pressuremay be risk factors for the development or progression of depression insuch patients.

In addition to chronic and/or acute SNS hyperactivity, increasedglucocorticoid (e.g., cortisol) levels, and HPA axis dysfunction, e.g.,as a measurement of basal cortisol levels in response to awakening as anindicator for endogenous stress response, provide additional riskfactors that can be considered in establishing a predictive riskassessment for the development of depression in a patient (Spijker, A.T. and van Rossum, E. F. C., Neuroendocrinology, 2012, 95:179-186). Forexample, an abnormally high measurement of cortisol awakening rise(CAR), which reflects the natural response to awakening with anormal/natural increase in cortisol levels, is not only characteristicof depressed patients, but is predictive for developing a majordepressive disorder within a year after sampling, and thereby providesan additional risk factor of subsequent depression development (Id.). Inaddition, patients without a history of depression but with parentsdiagnosed with depression, have demonstrated equally high CAR levels asthose patients with a current depression diagnosis (Id.). Without beingbound by theory, it is thought that high levels of cortisol resulting inglucocorticoid resistance and increased HPA axis activity fails toinhibit CRH/norepinephrine responses to stress and further exacerbatescognitive dysfunction (e.g., memory deficits) and depressive moodsymptoms in these individuals (Id.).

In addition to predisposition factors associated with activation of theSNS and other demographic risk factors, certain genetic variations amongindividuals have also been shown to be predictive risk factors for thedevelopment of depression. Some of these genetic risk factors are commonto both MDD and anxiety disorders. For example, genes that affect riskfor development of depression may also influence risk for otherpsychiatric disorders and vice versa. As with other mental disorders,influences on depression are likely polygenic; at least 17 singlenucleotide polymorphisms (SNPs) in 15 different genomic regions havebeen associated with depression in at least one published study (Hyde,C. L., et al., Nature Genet, 2016, 48: 1031-1036). These and othergenetic variants demonstrated to influence risk for depression includegenes involved in HPA axis regulation, the locus coeruleus/noradrenergicsystem, dopaminergic and serotonergic systems (e.g., regulation ofsynapses, monoamine metabolism, etc.) and other neurodevelopmentprograms (Hyde, C. L., et al., Nature Genet, 2016, 48: 1031-1036;Converge Consortium, Nature, 2015, 523: 588-591; Miller, A. H., et al.,Biol Psychiatry, 2009, 65: 732-741).

With respect to HPA axis regulation, several known genetic variations inthe glucocorticoid receptor gene, NR3C1, affect glucocorticoidsensitivity (Spijker, A. T. and van Rossum, E. F. C.,Neuroendocrinology, 2012, 95:179-186). For example, the ER22/23EKpolymorphism, which is associated with mild glucocorticoid resistance,and the BclI polymorphism, which is associated with increased stabilityof the mRNA of the dominant negative GR-β isoform, are both associatedwith a higher risk of developing a depressive episode (Id.).Additionally, carriers of particular heritable polymorphisms in thegenes encoding for FK506-binding protein 5 (FKBP5; co-chaperone of theglucocorticoid receptor that inhibits ligand binding and pathwayactivation) leading to increased intracellular FKBP5 protein expression,the CRH receptor 1 (CRHR1 rs242939 polymorphism), and serotonintransporter (SLC6A4; responsible for serotonin transport and reuptake)have been shown to be overrepresented in patients with depression, andcarriers of these genetic variants have an increased likelihood ofdeveloping depression (Spijker, A. T. and van Rossum, E. F. C.,Neuroendocrinology, 2012, 95:179-186; Miller, A. H., et al., BiolPsychiatry, 2009, 65: 732-741). Additionally, functional allelicvariants of the genes for IL-1β and TNF-α, and genes responsible forT-cell function, are associated with an increased risk for thedevelopment of depression and may further be associated with reducedresponsiveness to antidepressant therapy (Miller, A. H., et al., BiolPsychiatry, 2009, 65: 732-741).

Within the RAS pathway, ACE gene variants, which are characterized by aninsertion (allele I) or deletion (allele D) of a ˜250 basepair fragment,affect ACE activity. Patients with homozygous genotype DD present withhigher ACE activity and is associated with major depression and risk ofsuicidal behavior (Liu, F., et al., Int. J Physiol PathophysiolPharmacol, 2012, 4: 28-35). Additional SNPs (rs4291, rs4295) located inthe promoter region of the ACE gene are also associated with depressionand increased likelihood of developing depression (Id.). Further geneticvariants of the RAS pathway highly associated with depression includepolymorphisms of the AT₁R (e.g., A1166C polymorphism) (Id.).

Further evidence has suggested that in addition to genotype, epigeneticfactors such as gene methylation, histone deacetylation, and other geneexpression differences can influence or accompany the development ofdepression, and these genetic profiles can be screened to determinepatients presenting certain genetic pre-dispositions associated withhigh or increased risk of developing depression (Spijker, A. T. and vanRossum, E. F. C., Neuroendocrinology, 2012, 95: 179-186).

Once clinical depression is present, a host of physiological changesoccur, including SNS and immune system activation/hyperactivation,neuroendocrine changes, rhythm disturbances, oxidative stress, platelethypercoagulability and endothelial dysfunction, all of which exert anegative impact on cardiovascular health (Halaris, A., Curr Topics BehavNeurosci, 2017, 31:45-70). As discussed above, depression ischaracterized by, among other things, elevated SNS activity, reducedheart rate variability, increased plasma cortisol levels and elevatedinflammatory responses, all of which are associated with increased riskof cardiovascular disease (Brown, A. D., et al., CNS Drugs, 2009,23:583-602). In particular, psychological stress accompanying depressioncauses dysregulation of the SNS and the HPA axis which can precipitatenumerous downstream physiological effects throughout the body, includinghypertension, left ventricular hypertrophy, coronary vasoconstriction,endothelial dysfunction, platelet activation and the production ofpro-inflammatory cytokines, all of which carry an elevated risk ofventricular arrhythmias and MI (Dhar, A. K. and Barton, D. A., Front.Psychiatry, 2016, 7:33). Additionally, MDD has been shown to beassociated with increased morbidity and mortality in patients havingcardiovascular disease (Id.). Without being bound by theory, mentalstress (which accompanies depression) has been shown to activate cardiacsympathetic nerves with downstream effects of heart rhythm disturbances,increased risk of ventricular arrhythmias, decreased blood flow, leftventricular hypertrophy, MI and sudden death. Furthermore, essentialhypertension can be triggered by and maintained by chronic psychologicalstress. Accordingly, depression is a risk factor for the development ofcardiovascular disease and stroke, with the relative risk levelproportional to the severity of depression in the patient (Dhar, A. K.and Barton, D. A., Front. Psychiatry, 2016, 7:33; Brown, A. D., et al.,CNS Drugs, 2009, 23:583-602). Furthermore, chronic stress and depressivesymptoms in patients significantly increase future risk of stroke andtransient ischemic attacks (TIAs), with higher levels of depressivesymptoms proportional to the increased risk of stroke and TIA(Everson-Rose, S. A., et al., Stroke, 2014, 45: 2318-2323). Excessstroke and TIA risk associated with depression may stem fromdepression-associated activation of the HPA axis, elevatedcatecholamines, and elevated inflammatory responses (e.g., increasedCRP, IL-6, etc.) which are all related to stroke risk (Id.).

C. Identification of Patients or Cohorts Diagnosed with Depression or atRisk of Developing Depression

Patients presenting with a high likelihood of having depression caninclude patients presenting with one or more of (1) depression symptoms(e.g., depressed mood for most of the day, anhedonia, psychomotoragitation or retardation nearly every day, anergia, poor appetite orovereating, low self-esteem or feelings of worthlessness, changes incognitive ability, and/or negative feelings about self or the world),(2) sleep disturbances (e.g., insomnia, hypersomnia, difficultymaintaining sleep, etc.), (3) suicidal thoughts or tendencies, (4)personal history of one or more depressive episodes, and/or (5) priordiagnosis of a mood disorder (e.g., depression, anxiety, bipolar, panicdisorder, etc.). Patients demonstrating certain risk factors ordepressive symptoms may also have an increased likelihood of havingdepression if they exhibit with one or more of elevated SNS activity(e.g., catecholamines detected in urine or plasma), low central nervoussystem NPY levels, elevated cortisol levels, glucocorticoid resistance(e.g., as assessed via dexamethasone suppression test), elevated CAR,low heart rate variability, elevated MSBP, limited or no “dipping” ofnocturnal blood pressure, elevated levels of serum inflammatory cytokinelevels (e.g., IL-6, IL-1β, IL-2, TNF-α, CRP, etc.), and/or endothelialdysfunction.

Some patients may also present with comorbid conditions or diseases suchas cardiovascular disease, having suffered a major cardiac event (e.g.,MI, coronary artery bypass surgery), having had a stroke or risk ofstroke, hypertension or pre-hypertension, ventricular arrhythmias, leftventricular hypertrophy, above-normal cholesterol levels,atherosclerosis, insulin resistance or other metabolic disorder,arterial stiffening or aneurysm(s), obesity or being overweight (e.g.,high BMI), cancer, and/or patients with active substance abuse, ahistory of substance abuse, or prior mental disorder. In certainembodiments, the patient can present with one or more risk factorsand/or comorbid conditions associated with an increased likelihood ofhaving depression. However, in other embodiments, such associatedconditions may not be present in a patient having depression and/or atrisk of developing depression. For example, the patient may benormotensive, have no evidence of cardiovascular disease, normal BMI,normal insulin sensitivity, and/or no elevated levels of inflammatorybiomarkers.

Patients presenting with a high or increased risk of developingdepression can include patients having one or more demographic orbiophysical risk factors as described herein and who have not met thediagnosis standard as set forth in DSM-5 and/or patients in which one ormore depression screening tools or instruments used to give aprofessionally-accepted diagnosis have not confirmed depression.However, such patients may present one or more risk factors associatedwith an increased likelihood of developing depression. For example, thepatient may have an increased likelihood of a present conditionprogressing to depression, such as a patient presenting some but not aqualifying number of symptoms on the DSM-5, or in another embodiment, apatient may present a qualifying number of symptoms but has notexperienced a threshold level of severity for one or more of thosesymptoms. In another example, the patient may demonstrate a combinationof depression risk factors (e.g., elevated SNS tone, high CAR,glucocorticoid resistance, elevated levels of CRP, low levels of centralNPY, having experienced prior depressive episodes, history of childabuse or trauma, and/or family history of depression or other mentalillness, etc.) and currently be experiencing chronic and/or excessivepsychological stress (e.g., experiencing major life change, a difficultrelationship, illness or disease of self or loved one, death of lovedone, occupational stress, etc.).

In particular embodiments, patients having an increased risk ofdeveloping moderate or severe depression may have, for example, milddepression and demonstrate one or more of the following risk factors:(1) fewer than five DSM-5 depression symptoms (e.g., depressed mood formost of the day, anhedonia, psychomotor agitation or retardation nearlyevery day, anergia, poor appetite or overeating, low self-esteem orfeelings of worthlessness, changes in cognitive ability, and/or negativefeelings about self or the world, etc.), (2) sleep disturbances (e.g.,insomnia, hypersomnia, difficulty maintaining sleep, etc.), (3) suicidalthoughts or tendencies, (4) personal history of one or more depressiveepisodes, (5) prior diagnosis of a mood disorder (e.g., depression,anxiety, bipolar, panic disorder, etc.) and/or (6) family history ofdepression or mental illness. Further risk factors for the developmentof depression in patients can include physiological markers such aselevated SNS activity (e.g., increased levels of catecholamines asdetected in urine or plasma), elevated cortisol levels, low centralnervous system NPY levels, glucocorticoid resistance (e.g., as assessedvia dexamethasone suppression test), elevated CAR, low heart ratevariability, elevated MSBP, limited or no “dipping” of nocturnal bloodpressure, low baroreceptor sensitivity (e.g., an assessment ofcardiovascular autonomic neuropathy), and/or elevated levels of seruminflammatory cytokine levels. A patient at-risk of developing depressionmay be hypertensive or pre-hypertensive and/or show elevated SNS tone inthe form of blood pressure dysregulation (e.g., elevated 24-hour bloodpressure variability). However, in many instances, patients havingdepression or being at-risk of developing depression can have normalblood pressure levels (e.g., do not have hypertension orpre-hypertension).

In some embodiments of the present technology, the patient can have acalculated risk score for determining depression status (e.g.,diagnosis, severity, etc.) or for the prediction of developingdepression that is above a threshold depression risk score. Such acalculated depression risk score can indicate a likelihood of depressiondiagnosis or, in another embodiment, a likelihood of developingdepression. In one embodiment, for example, a calculated depression riskscore for determining depression status can be based upon one or moredata sets known in the art. For example, a depression risk score basedupon the Major Depression Inventory (MDI) assessment, derived data fromtwo randomized, double-blind trials (Bech, P., et al., BMC Psychiatry,2015, 15:190). The MDI can be used to establish a depression risk scorefor determining depression status (e.g., diagnosis/severity), and can bebased upon an analysis of the patient's assessment across multiplepossible risk factors (Id.). For example, the patient can be queried andassessed for core depression symptoms indicated in the DSM-5 and theInternational Statistical Classification of Diseases and Related HealthProblems (ICD-10) classification systems to determine if a patient hasmild, moderate, or severe depression. One of ordinary skill in the artwill recognize that the MDI study is only one study in which a riskscore calculation can be developed and applied. For example, the FPArisk score model was developed for identifying risk factors fordepression and for predicting a likely diagnostic configuration ofdepression symptoms to provide qualitative information about thepatient's specific clinical features (Serra, F., et al., Front. Psychol,2017, 8, 214). Other published data sources documenting multiplepossible risk factors and corresponding scores may use any of many welldescribed techniques. Such techniques for developing tools to calculatea depression risk score could be empirical, based on multivariateregression, or using artificial intelligence (e.g. Bayesian probability,machine learning, etc.) among other techniques known in the art.

In other embodiments, a patient presenting a high or increased risk ofdeveloping depression can have a genetic disorder or determined geneticpre-disposition to developing depression. For example, specific forms(e.g., polymorphisms) of the glucocorticoid receptor gene, NR3C1, affectglucocorticoid sensitivity and are associated with increased risk ofdeveloping a depressive episode (Spijker, A. T. and van Rossum, E. F.C., Neuroendocrinology, 2012, 95:179-186). Additional polymorphisms inthe gene known as FKBP5, a co-chaperone of the glucocorticoid receptor,is associated with increased glucocorticoid resistance and increasedrisk for depression (Id.). Additionally, carriers of polymorphisms inthe genes encoding for the CRH receptor 1, the serotonin transporter,IL-113, TNF-α, ACE, and the angiotensin II receptor, AT₁R, areassociated with an increased likelihood of developing depression(Spijker, A. T. and van Rossum, E. F. C., Neuroendocrinology, 2012,95:179-186; Miller, A. H., et al., Biol Psychiatry, 2009, 65: 732-741;Liu, F., et al., Int J Physiol Pathophysiol Pharmacol, 2012, 4: 28-35).As evidence has suggested that genotype, gene methylation, histonedeacetylation, and gene expression differences among other epigeneticfactors, influence or accompany the development of depression, thesegenetic profiles can be screened to determine patients presentingcertain genetic pre-dispositions associated with high or increased riskof developing depression (Spijker, A. T. and van Rossum, E. F. C.,Neuroendocrinology, 2012, 95:179-186).

A patient suspected of having depression can be evaluated for a level ofdysfunction or severity of symptoms and/or sequelae associated withdepression. Evaluation of core depression symptoms (e.g., feelings ofsadness, apathy, mood swings, loss of interest or pleasure inactivities, guilt, anxiety, excess sleepiness, fatigue, excessivehunger, loss of appetite, irritability, excessive crying, lack ofconcentration, slowness in activity and thoughts of suicide in thepatient, etc.), sleep disturbances (e.g., insomnia, restless sleep),etc. can include a self-reporting or assessment of changes from aperson's usual level of function (e.g., prior to on-set of symptoms) toa current condition. Evaluation input may also come from trusted sources(e.g., trusted family members, friends, primary physician, etc.) thatcan provide information on changes in performance on daily activities,job/employment performance, behavior or mood changes, sleep patterns, aswell as angry outbursts, irritability or aggression and/or other riskyor destructive behaviors, etc.

Physicians or other qualified clinicians may also administer one or morequestionnaires or diagnostic tests, such as screening tools, to assessdepression risk, severity and diagnosis. Depression screening tools suchas the MDI, PHQ-9, MINI, HAM-D₁₇, MES, Zung-SDS, BDI-II, and/or a VAS,among others, as well as other screening instruments, such as the FPA,that look at multiple risk factors for predicting the patient-specificclinical features along with depression status can be utilized in theassessment process. One of ordinary skill in the art will recognizeother depression tests and scales that can be used to determine statusof depression of a patient. In some embodiments, for example, a patientmay be suspected of having depression based upon a single test score oroutcome, combined test scores from multiple tests, or one or more testscores from multiple tests. Diagnosis can be made based upon, forexample, meeting or exceeding a threshold test score. In otherembodiments, a patient may demonstrate an increase in symptom severityas reflected in test scores taken over time. For example, a particularpatient may show an increase in depression risk via a result in a testscore between taking tests two weeks after on-set of symptoms, one monthafter on-set of symptoms, six months after on-set of symptoms, and ayear or more after on-set of symptoms. Cognitive functioning (e.g.,cerebral activities encompassing reasoning, memory, attention, andlanguage), emotional/social functioning (e.g., traits and abilitiesinvolving positive and negative aspects of social and emotional lifelike empathy, interpreting emotion, speed and intensity of emotiongeneration, and efficacy of coping with negative emotions, etc.), andanxiety levels, as well as other data that can be collected in anevaluation of a patient, are based on self-report, observational(behavioral), or psychological data.

In a particular example, if a patient could respond (or a cliniciancould so indicate with respect to a patient) in affirmation (i.e.,answering “yes”) to five or more of the following questions, then thepatient could be diagnosed with depression and, in some embodiments, betreated with renal neuromodulation to treat the depression: Over thepast two weeks and at least most of the time—

-   -   1. Have you felt low in spirits or sad?    -   2. Have you lost interest in your daily activities?    -   3. Have you felt lacking in energy and strength?    -   4. Have you felt less self-confident?    -   5. Have you had a bad conscious or feelings of guilt?    -   6. Have you felt that life wasn't worth living?    -   7. Have you had difficulty in concentrating, e.g., when reading        the newspaper or watching television?    -   8a. Have you felt very restless?    -   8b. Have you felt subdued or slowed down?    -   9. Have you had trouble sleeping at night?    -   10a. Have you suffered from reduced appetite?    -   10b. Have you suffered from increased appetite?

Additional screening tools or depression risk score calculating toolsmay ask additional questions to identify the presence or absence ofknown depression risk factors. For example, a patient may be asked torespond to one or more of the following questions in an assessment:

-   -   Do you have a personal or family history of depression or mental        illness?    -   How many adverse life events (e.g., major illness, abuse, loss        of a loved one, unemployment, psychological trauma, etc.) have        you experienced that has caused you either high levels of stress        or chronic (e.g., greater than one year) stress?    -   Did you experience traumatic life events and/or abuse as a child        or adolescent?    -   Do you have difficulty falling asleep or staying asleep?    -   Are you single, married, widowed or divorced?    -   Do you have family or other social support in your life?

In addition to self-reporting, observational, or other psychologicaldata, a patient may also be evaluated for physiological data.Accordingly, a patient may demonstrate one or more physiologicalparameters associated with depression or, in other embodiments, withchronic psychological stress. Non-limiting examples ofdepression-associated physiological parameters may include low heartrate variability (e.g., as assessed by Standard Deviation NN intervals(SDNN)), decreased baroreceptor sensitivity (as an assessment ofcardiovascular autonomic neuropathy), heightened heart rate responses tostimuli/stress (e.g., via Stroop Color Test or Cold Pressor Test),elevated muscle sympathetic nerve activity (MSNA; a marker of SNSactivity), elevated systolic blood pressure, increased MSBP, lack of orlow levels of nocturnal blood pressure “dipping”, higher skinconductance (e.g., a measure of sweat activity thought to be under SNSinfluence), higher resting heart rate, disrupted sleep patterns or lowquality sleep, elevated peripheral inflammatory markers (e.g., IL-6,IL-1β, IL-2, CRP, TNF-α, etc.), low NPY levels (e.g., in the CNS andplasma), and other measures of sympathetic activity (e.g., increasedrenal and/or total body norepinephrine spillover, increased plasmanorepinephrine levels, increased urine levels of norepinephrine andmetabolites thereof, etc.). Further physiological parameters that can berisk factors for depression may include increased cortisol levels,glucocorticoid resistance (e.g., as assessed via dexamethasonesuppression test), reduced hippocampal volume (e.g., as assessed bystructural magnetic resonance imaging (sMRI)), and/or decreased levelsof neurotransmitter receptors (e.g., GABA, 5-HT/serotonin, dopamine) inthe brain (e.g., as assessed via administered radioligands followed bypositron emission tomography (PET)), (Bearden, C. E., et al., ASN Neuro,2009, 1(4): art: e00020. doi:10.1042/AN20090026; Pitman, R. K., et al.,Nat Rev Neurosci., 2012, 13: 769-787).

In accordance with aspects of the present technology, patientspresenting with one or more risk factors for having depression, having acalculated depression risk score, and/or one or more risk factors fordeveloping depression can be candidates for treatment for depression. Inother embodiments, some patients may also be candidates for renalneuromodulation for the prevention of developing depression in thepatient. As noted above, renal neuromodulation is expected toefficaciously treat depression including one or more symptoms associatedwith depression. Renal neuromodulation is also expected to efficaciouslyprevent an incidence of, reduce a severity of, or slow a progression ofdepression. Renal neuromodulation is further expected to improve apatient's calculated depression risk score correlating to a depressionstatus/diagnosis.

In certain embodiments, for example, renal neuromodulation treatsseveral clinical conditions characterized by increased overallsympathetic activity and, in particular, conditions associated withcentral sympathetic overstimulation such as pre-hypertension,hypertension, blood pressure variability, heart rate variability,vascular disease (e.g., vessel stiffening), metabolic syndrome, insulinresistance, diabetes, cancer, cognitive impairment (e.g., which canprogress to dementia), and systemic inflammation, among others, that maybe associated with and/or contribute to a severity or progression ofdepression in a patient. The reduction of afferent neural signalstypically contributes to the systemic reduction of sympathetictone/drive, and renal neuromodulation is expected to be useful intreating several conditions associated with systemic sympatheticoveractivity or hyperactivity. For example, and in accordance with otheraspects of the present technology, patients presenting with one or morerisk factors for having depression and/or having a positive clinicaldiagnosis for depression can be candidates for renal neuromodulationtreatment for preventing, reducing an incidence of, and/or reducing aseverity of a cardiovascular condition (e.g., coronary heart disease,MI, left ventricular hypertrophy, ventricular arrhythmias, etc.) and/orstroke (e.g., acute ischemic stroke, lacunar stroke, transient ischemicattack (TIA), hemorrhagic stroke, etc.) in the patient. In otherembodiments, treating patients having depression in younger (e.g., 18-40years of age) or in middle-aged (e.g., 40-65 years of age) patients mayreduce an incidence of or improve an outcome of many comorbid conditionsand diseases including, but not limited to, cardiovascular disease,stroke, metabolic disorders, diabetes, obesity, cancer, dementia, etc.Accordingly, in particular examples, patients having or at risk ofhaving depression and who are suitable candidates for treatment viarenal neuromodulation can be between the ages of 18 and 45, between theages of 18 and 30, between the ages of 20 and 40, or between the ages of20 and 35. In other embodiments, the patients may be between the ages of35 and 65, between the ages of 45 and 65, between the ages of 50 and 70,or the patient can be at least 35 years old.

II. RENAL NEUROMODULATION FOR TREATING DEPRESSION AND/OR REDUCING A RISKASSOCIATED WITH THE DEVELOPMENT OF DEPRESSION

Therapeutically-effective renal neuromodulation can be used for thetreatment of depression or for the treatment of one or more symptomsand/or sequelae associated with depression, the management ofdepression, or to reduce an incidence of depression in patientsidentified as having a risk of developing depression at a future time.In further embodiments, therapeutically-effective renal neuromodulationcan be used for treating a patient (e.g., a patient having one or morerisk factors associated with developing depression) prior toexperiencing a potentially severe or life-threatening episode (e.g., newor potential mother at risk of developing severe postpartum depression,patient with one or more suicide attempts during previous depressiveepisode) for reducing a risk associated with developing depression.

In other embodiments, therapeutically-effective renal neuromodulationcan be used to treat depressed patients or patients diagnosed withdepression to reduce an incidence of cardiovascular disease (e.g.,coronary heart disease, etc.) or a cardiovascular event (e.g., MI,stroke, etc.) in the patient. In further embodiments,therapeutically-effective renal neuromodulation can be used for treatinga patient having depression to improve one or more parameters associatedwith cardiovascular health, or to reduce a severity of a cardiovascularcondition.

While sympathetic drive regulation can have adaptive utility inmaintaining homeostasis or in preparing many organs in the body for arapid response to environmental factors, chronic activation of the SNS(e.g., associated with acute stress syndrome, chronic stress, primaryaging, age-associated obesity, etc.) is a common maladaptive responsethat can contribute to diseases/conditions (e.g., hypertension, systemicor localized inflammation, vascular remodeling, atherosclerosis,obesity, insulin resistance, metabolic syndrome, etc.) or predisposeindividuals to psychophysiological adaptations that can increase apatient's risk of developing depression and/or drive progression and/orseverity of depression in a patient. Excessive activation of the renalsympathetic nerves in particular has been identified experimentally andin humans as a likely contributor to the complex pathophysiology ofhypertension, states of volume overload (such as heart failure),systemic inflammation, and progressive renal disease. As examples,radiotracer dilution has demonstrated increased renal norepinephrinespillover rates in patients with essential hypertension.

Aspects of the present technology include targeting renal nerve fibersfor neuromodulation in patients (1) having been diagnosed withdepression, (2) demonstrating one more physiological and/orpsychological symptoms associated with depression, and/or (3) having anincreased risk associated with developing depression. Targeting renalnerve fibers for neuromodulation in patients can effectively attenuateneural traffic along the sympathetic nerves. Without being bound bytheory, attenuation of neural traffic along renal sympathetic nerves canbe used, for example, to treat or prohibit one or more hallmark symptomsassociated with depression, decrease systemic inflammatory responsesassociated with depression, and/or decrease a level of severity ofdepression and/or reduce a number of symptoms associated with depressionin the patient. In some embodiments, hallmark symptoms of depressionthat can be treated, reduced or prevented via attenuation of neuraltraffic along renal sympathetic nerves can include, for example,depressed mood for most of the day, anhedonia, psychomotor agitation orretardation nearly every day, anergia, poor appetite or overeating, lowself-esteem or feelings of worthlessness, changes in cognitive ability,and/or negative feelings about self or the world, sleep disturbances(e.g., insomnia, hypersomnia, difficulty maintaining sleep, etc.),suicidal thoughts or tendencies, and undesirable elevations in heartrate, blood pressure, and inflammation. In yet another embodiment,attenuation of neural traffic along renal sympathetic nerves in anindividual having one or more risk factors associated with developingdepression can be used for reducing a risk associated with developingdepression.

As discussed above, several diseases and conditions have highcomorbidity with depression diagnosis, including, for example, substanceand alcohol abuse/addiction, anxiety disorder, panic disorder,cardiovascular disease, stroke, hypertension, obesity (e.g., high BMI),metabolic disorders, such as type 2 diabetes, cancer, and cognitiveimpairment (e.g., leading to dementia). In certain embodiments, patientshaving depression and one or more comorbid conditions and/or diseasescan be treated with renal neuromodulation to treat and/or reduceseverity of the depression and/or the one or more comorbidconditions/diseases. In another example, renal neuromodulation can beused to therapeutically treat a patient diagnosed with depression forpreventing and/or reducing an incidence of developing one or morecomorbid conditions/diseases, including those conditions/diseaseswherein chronic SNS activity is known to be a contributing factor (e.g.,hypertension, cardiovascular disease, etc.).

In one example, renal neuromodulation can be used to reduce a patient'ssystolic blood pressure, including a MSBP and/or a nocturnal bloodpressure level. In another example, renal neuromodulation can be used toincrease heart rate variability (e.g., the beat-to-beat fluctuations inheart rate) in a patient. In other embodiments, attenuation of neuraltraffic along renal sympathetic nerves can be used to treat or preventmetabolic disorders, obesity and/or insulin resistance in the patienthaving depression or at increased risk associated with developingdepression. In yet a further embodiment, renal neuromodulation can beused to lower one or more levels of inflammatory biomarkers in apatient.

Certain effects of chronic SNS activation (such as resulting fromchronic psychological stress) that take place prior to experiencing apotential depressive episode may be associated with an increased risk ofdeveloping depression. Many of these effects may not yield noticeablesigns or symptoms associated with a disease; however, the effects ofchronic SNS activation can cause unseen damage to cardiac tissue, braintissue, and/or vascular tissue, as well as disrupt normalneurophysiological and hormonal balances throughout the body prior tothe appearance of quantifiable disease indicators typically associatedwith maladaptive SNS activation and/or prior to exposure to experiencingdepression-associated symptoms in the predisposed or at-risk individual.Accordingly, in one embodiment, neuromodulation treatment can be used totreat patients having a high risk of developing depression. For example,patients may present one or more risk factors for developing depression(e.g., having been diagnosed with chronic stress, having an elevatedheart rate, having reduced heart rate variability, having elevatedcortisol levels and/or CRH levels, presenting with glucocorticoidresistance, elevated CAR, low levels of central NPY, having elevatedsystemic plasma levels of inflammatory biomarkers (e.g., IL-6, CRP,etc.), having high blood pressure, having a genetic predisposition(e.g., polymorphisms in genes encoding for NR3C1, FKBP5, CRHR1, SLC6A4IL-1β, TNF-α, ACE, AT₁R, etc.). In other examples, such patients havinga high risk of developing depression may present one or more social ordemographic risk factors for the development of depression (e.g.,adverse childhood experience(s), female gender, single, personal orfamily history of depression or mental illness, experiencing adverselife events, prior exposure to trauma, history of substance abuse, beingin a stressful situation or relationship, low level of education,smoker, physically inactive, etc.).

In still further embodiments, neuromodulation treatment can be used totreat patients for improving a depression risk score for a patientdiagnosed with depression. Such a risk score may be determined, forexample, using a depression-screening tool for determining a severity ofdepression in the patient. For example, certain patients can have adepression risk score above a threshold depression risk score, can haveone or more depression risk factors, have a combination of depressionrisk factors, etc., and renal neuromodulation can be used totherapeutically reduce (a) systemic plasma levels of norepinephrinefrom, e.g., spillover from innervation of smooth muscle surroundingblood vessels, (b) systemic plasma levels of inflammatory biomarkers(e.g., IL-6, CRP, etc.), and/or (c) high blood pressure. In otherembodiments, neuromodulation treatment can be used to increase heartrate variability or decrease MSBP in patients.

In one embodiment, a patient having extreme or chronicpsychological/mental stress in response to an adverse life event orcondition and presenting with one or more acute stress indicators orother indicators, such as pre-hypertension (e.g., systolic BP of 120-139mmHg/diastolic BP of 80-89 mmHg), hypertension (e.g., systolic BP>140mmHg/diastolic BP>90 mmHg), increased serum levels of IL-6 or CRP,higher levels of glucocorticoid (e.g., cortisol), higher CAR, higherMSBP, decreased heart rate variability, or having other factorspresenting an increased risk of developing depression (e.g., personshaving experienced traumatic events, adverse childhood, family historyof mental illness, depression-associated genetic polymorphisms, etc.)can be treated with renal neuromodulation to reduce a level of renalsympathetic drive and/or reduce a level of systemic norepinephrinespillover in circulating plasma (Schlaich, M. P., et al., Frontiers inPhysiology, 2012, 3(10): 1-7).

In some embodiments, a patient demonstrating chronic stress indicatorsfor greater than 1 year and presenting with depression-associatedsymptoms can be diagnosed with depression by a physician or qualifiedclinician. In other embodiments, a patient demonstrating chronic stressindicators and depression-associated symptoms can present with aqualifying result on a depression screening tool (e.g., tool forassessing depression diagnosis, tool for assessing depression riskstatus, etc.). In further embodiments, chronic psychological stressindicators precipitated by an adverse life condition or event can referto patients at risk of developing depression, and patients may betreated with renal neuromodulation to prevent a future on-set ofdepression, reduce a risk factor score associated with the severity ofdepression, reduce a severity of one or more symptoms associated withdepression, or reduce an incidence of developing one more comorbidconditions/diseases.

Several embodiments of the present technology utilize intravasculardevices that reduce sympathetic nerve activity by applying, for example,radiofrequency (RF) energy to target nerve(s) or target site(s) inpatients presenting one or more physiological symptoms associated withdepression, or having a risk of developing depression, such as havingone or more depression risk factors. In certain embodiments,neuromodulation is used to reduce renal sympathetic nerve activity inpatients having a high risk (e.g., a predisposition or increasedlikelihood) of developing depression, one or more signs or symptomsassociated with depression development, or, in further embodiments, inpatients having been diagnosed with depression. In a particularembodiment, neuromodulation is used to reduce renal sympathetic nerveactivity in patients having a depression risk score (e.g., indicating astatus or severity of depression) above a threshold risk score.

Renal neuromodulation is the partial or complete incapacitation or othereffective disruption of the nerves of the kidneys, including nervesterminating in the kidneys or in structures closely associated with thekidneys. In particular, renal neuromodulation can include inhibiting,reducing, and/or blocking neural communication along neural fibers(i.e., efferent and/or afferent nerve fibers) innervating the kidneys.Such incapacitation can be long-term (e.g., permanent or for periods ofmonths, years, or decades) or short-term (e.g., for periods of minutes,hours, days, or weeks). While long-term disruption of the renal nervescan be desirable for preventing incidence of or treating depression,reducing a severity of depression, or for alleviating symptoms and othersequelae associated with depression over longer periods of time,short-term modulation of the renal nerves may also be desirable. Forexample, some patients may benefit from short-term renal nervemodulation to address acute symptoms presenting during or following anadverse life event or condition, such as hyperarousal, social or otheranxiety, insomnia, mood swings, or other stress/anxiety-relatedbehavioral changes. In particular, some patients may benefit fromshort-term renal nerve modulation to address the effects of grief, guiltor feelings of hopelessness following a traumatic event such as, forexample, an accident or natural disaster or loss of a loved one. Inother instances, some patients may benefit from short-term renal nervemodulation as adjuvant therapy to increase effectiveness ofco-administered drugs (e.g., antidepressant drugs, anti-psychotic drugs,anti-anxiety drugs, anti-inflammatory medications, anti-hypertensivedrugs, and sleeping medications among others administered to supportpatients with depression) and/or psychotherapy (e.g.,cognitive-behavioral therapy, interpersonal therapy, etc.).

FIG. 3 is an enlarged anatomic view of nerves innervating a left kidney50 of a patient. As FIG. 3 shows, the kidney 50 is innervated by a renalplexus 52, which is intimately associated with a renal artery 54. Therenal plexus 52 is an autonomic plexus that surrounds the renal artery54 and is embedded within the adventitia of the renal artery 54. Therenal plexus 52 extends along the renal artery 54 until it arrives atthe substance of the kidney 50, innervating the kidneys whileterminating in the blood vessels, the juxtaglomerular apparatus, and therenal tubules (not shown). Fibers contributing to the renal plexus 52arise from the celiac ganglion (not shown), the superior mesentericganglion (not shown), the aorticorenal ganglion 56 and the aortic plexus(not shown). The renal plexus 52, also referred to as the renal nerve,is predominantly comprised of sympathetic components. There is no (or atleast very minimal) parasympathetic innervation of the kidney 50.

Preganglionic neuronal cell bodies are located in the intermediolateralcell column of the spinal cord (renal sympathetic nerves arise fromT10-L2, FIG. 1). Referring to FIGS. 1 and 3 together, preganglionicaxons pass through the paravertebral ganglia (they do not synapse) tobecome the lesser splanchnic nerve, the least splanchnic nerve, thefirst lumbar splanchnic nerve, and the second lumbar splanchnic nerve,and they travel to the celiac ganglion (FIG. 1), the superior mesentericganglion (FIG. 1), and the aorticorenal ganglion 56. Postganglionicneuronal cell bodies exit the celiac ganglion, the superior mesentericganglion, and the aorticorenal ganglion 56 to the renal plexus 52 andare distributed to the renal vasculature.

It has previously been shown that stimulation of renal efferent nervesdirectly affects neural regulation components of renal function that areconsiderably stimulated in disease states characterized by heightenedsympathetic tone such as, for example, increased blood pressure inhypertensive patients. As provided herein, renal neuromodulation islikely to be valuable in the treatment of depression and/or symptomsassociated with depression. Renal neuromodulation is also likely to bevaluable in the prevention of developing depression in certain at-riskindividuals (e.g., individuals having experienced adverse life events orcircumstances and/or presenting one or more chronic stress indicators orbiomarkers indicating a high likelihood of developing depression).

Renal neuromodulation may also likely to be valuable in the treatment ofdiseases and conditions that are associated with depression and/orincreased SNS tone such as, for example, cardiovascular disease,hypertension, increased blood pressure variability, systemicinflammation, endothelial dysfunction, vascular inflammation, vesselremodeling and/or hardening, atherosclerosis, and metabolic disordersamong others. In particular, renal neuromodulation along the renalartery and/or within branches of the renal artery as described in U.S.patent application Ser. No. 14/839,893, filed Aug. 28, 2015 andincorporated herein by reference in its entirety, is expected to reducerenal sympathetic drive in the kidney, thereby reducing the negativeimpact of SNS activation on aspects of these and other conditionsassociated with physiological changes that have impact on psychologicaland cognitive health. As such, renal neuromodulation is also likely tobe particularly valuable in patients having one or more clinicalconditions characterized by increased overall and particularly renalsympathetic activity, such as cardiovascular disease, hypertension,increased blood pressure variability, low heart rate variability,systemic inflammation, chronic vascular inflammation, endothelialdysfunction, metabolic syndrome, insulin resistance, diabetes, anxietydisorder, and depression among others.

As the reduction of afferent neural signals contributes to the systemicreduction of sympathetic tone/drive, renal neuromodulation might also beuseful in preventing depression. For example, a reduction in centralsympathetic drive may reduce and/or improve measurable physiologicalparameters typically associated with the development of depression,prior to on-set of core depression symptoms. Alternatively, a reductionin central sympathetic drive may, for example, reduce an elevated heartrate, improved blood pressure, improve heart rate variability, increaseblood flow to the brain, reduce cerebrovascular inflammation, reducesystemic inflammation, and/or improve other chronic stress-relatedsymptoms such as generalized anxiety and sleep disturbances (e.g.,insomnia, difficulty maintaining sleep, etc.).

Other psychologically and/or neurologically related conditions, such as,e.g., chronic anxiety, panic disorder (e.g., frequent panic attacks),and insomnia, as well as other conditions presented as comorbid withdepression such as, for example, cardiovascular disease, stroke,hypertension, high BMI (e.g., obesity), and metabolic disorder (e.g.,diabetes), may also be treatable or preventable in depressed patientsusing renal neuromodulation. In some instances,therapeutically-effective renal neuromodulation may improve one or moremeasurable physiological parameters associated with a comorbid diseaseor condition in the depressed patient without substantially improvingthe depression in the patient.

Intravascular devices that reduce sympathetic nerve activity byapplying, for example, RF energy to a target site in the renal arteryhave recently been shown to reduce blood pressure in patients withtreatment-resistant hypertension. The renal sympathetic nerves arisefrom T10-L2 and follow the renal artery to the kidney. The sympatheticnerves innervating the kidneys terminate in the blood vessels, thejuxtaglomerular apparatus, and the renal tubules. Stimulation of renalefferent nerves results in increased renin release (and subsequentrenin-angiotensin-aldosterone system (RAAS) activation) and sodiumretention and decreased renal blood flow. These neural regulationcomponents of renal function are considerably stimulated in diseasestates characterized by heightened sympathetic tone and likelycontribute to increased blood pressure in patients with depression andincreased levels of peripheral inflammatory markers, such as IL-6 andCRP, in patients with depression experiencing a host of inflammatorychallenges (Dhar, A. K. and Barton, D. A., Front. Psychiatry, 2016,7:33).

Pharmacologic strategies to thwart the consequences of renal efferentsympathetic stimulation include centrally acting sympatholytic drugs,beta blockers (intended to reduce renin release), angiotensin convertingenzyme inhibitors and receptor blockers (intended to block the action ofangiotensin II and aldosterone activation consequent to renin release),and diuretics (intended to counter the renal sympathetic mediated sodiumand water retention). These pharmacologic strategies, however, havesignificant limitations including limited efficacy, compliance issues,side effects, and others. Recently, intravascular devices that reducesympathetic nerve activity by applying an energy field to a target sitein the renal blood vessel (e.g., via radio frequency (RF) ablation) havebeen shown to be efficacious in reducing blood pressure, decreasingblood pressure variability, decreasing nocturnal blood pressure,reducing MSBP, improving arterial stiffness and reducing mediators ofsystemic inflammation in patients with treatment-resistant hypertension(Dörr, O., et al., Clin Res Cardiol, 2015, 104: 175-184; Zuern, C. S.,et al., Front. Physiol, 2012, 3(134): 1-8; Baroni, M., et al., HighBlood Press Cardiovasc Prev, 2015, (4):411-6; Brandt, M. C., et al.,JACC, 2012, 60(19): 1956-65; Mortensen, K., et al., J Clin Hypertens,2012, 14(12): 861-870; Kario, K., et al., Hypertension, 2015,66:1130-1137).

Various techniques can be used to partially or completely incapacitateneural pathways, such as those innervating the kidney. The purposefulapplication of energy (e.g., electrical energy, thermal energy) totissue can induce one or more desired thermal heating and/or coolingeffects on localized regions along all or a portion of a renal bloodvessel (e.g., renal artery, renal arterial branch, renal ostium, renalvein) and adjacent regions of the renal plexus RP, which lay intimatelywithin or adjacent to the adventitia of the renal blood vessel. Someembodiments of the present technology, for example, includeelectrode-based or transducer-based approaches, which can be used fortherapeutically-effective neuromodulation. For example, an energydelivery element (e.g., electrode) can be configured to deliverelectrical and/or thermal energy at a treatment site.

By way of theory, targeting both general afferent and efferent renalsympathetic nerves (e.g., via a catheter-based approach, utilizingextracorporeal ultrasound) may cause beneficial effects extending wellbeyond affecting a severity of depression or a risk associated withdeveloping depression, such as reducing a risk of developinghypertension, stroke, cardiovascular disease, obesity, metabolicdisorder or other end organ damage. As discussed herein, a correlationbetween hyperactivity of the SNS and an increased risk of developingdepression and an increased risk in promoting more severe depressionsymptoms has been implicated. There is now also evidence that depressionand related symptom severity is associated with chronic inflammatoryresponses and sympathetic activation appears to affect serum levels ofperipheral inflammatory markers. Additionally, chronic stress, obesityand other cardiovascular maladies promote hyperactivity (e.g.,overactivity) of the sympathetic nervous system throughout the body. Forexample, when experiencing stress, including chronic stress, hormonaland neural information (e.g., sensory afferent input) is received by theCNS, which in turn further elevates sympathetic tone via efferentsignaling throughout the body. Some aspects of methods of treatingpatients having depression or having one or more risk factors, includinga high risk score, for the development of depression, using sympatheticneuromodulation are at least in part derived from the recognitiondescribed herein that the kidneys may contribute to elevated centralsympathetic drive.

Several aspects of the current technology are configured to reduce renalsympathetic nerve activity within or near the kidney(s) to reducelocalized release of norepinephrine. Several properties of the renalvasculature may inform the design of treatment devices and associatedmethods for achieving target sympathetic neuromodulation, for example,via intravascular access, and impose specific design requirements forsuch devices. Specific design requirements for renal neuromodulation mayinclude accessing the renal artery, a ureter, a renal pelvis, a majorrenal calyx, a minor renal calyx, and/or another suitable structure;facilitating stable contact between the energy delivery elements of suchdevices and a luminal surface or wall of the suitable targetedstructure, and/or effectively modulating the renal nerves with theneuromodulatory apparatus.

Intravascular devices that reduce sympathetic nerve activity byapplying, for example, RF energy to a treatment site in the renal arteryhave recently been shown to reduce renal sympathetic drive, renalnorepinephrine spillover, and whole body norepinephrine spillover. Renalneuromodulation is expected to reduce renal sympathetic neural activity,and since the reduction of afferent neural signals contributes to thesystemic reduction of sympathetic tone/drive, renal neuromodulation is auseful technique in addressing certain risk factors and symptomsassociated with depression that are attributable to systemic sympathetichyperactivity. For example, as previously discussed, a reduction incentral sympathetic drive may treat depression including reducing aseverity of one or more symptoms associated with depression, reduce alikelihood of developing depression, as well as improve other comorbiddisease manifestations (e.g., hypertension, cardiovascular disease,stroke, metabolic disorders, insulin resistance, diabetes, systemicinflammation, generalized anxiety, panic attacks, etc.) associated withsympathetic hyperactivity.

Accordingly, renal neuromodulation is expected to be useful in treatingdepression, reducing a severity of one or more symptoms in patientsafflicted with depression, preventing and/or treating one or morecomorbid conditions or diseases associated with depression or preventingan incidence of developing depression in patients presenting certainrisk factors. The beneficial effect of renal neuromodulation withrespect to a risk associated with development of depression is expectedto apply to patients who do not currently meet the diagnostic standardfor a depression diagnosis (e.g., under DSM-5), for example, regardlessof the baseline renal sympathetic neural activity or the baseline levelof norepinephrine in plasma (e.g., whole body norepinephrine spillover).For example, renal neuromodulation in accordance with embodiments of thepresent technology can improve one or more measurable physiologicalparameters corresponding to a depression risk factor or status (e.g.,level of severity of diagnosis) in the patient when baseline renalsympathetic neural activity is normal, below normal, or above normal(e.g., hyperactive or overactive). Likewise, renal neuromodulation inaccordance with additional embodiments of the present technology canimprove one or more measurable physiological parameters corresponding toa depression risk factor or depression status (e.g., level of severityof diagnosis) in the patient when baseline central sympathetic drive,baseline norepinephrine spillover in plasma, and/or whole bodynorepinephrine spillover is normal, below normal, or above normal (e.g.,hyperactive or overactive). Such an improvement in one or moremeasurable physiological parameters corresponding to a depression riskfactor or depression status (e.g., level of severity of diagnosis) inthe patient can reduce a risk associated with developing depression inthat patient or can reduce symptom severity and/or effectively treat anafflicted patient diagnosed with depression.

III. METHODS FOR TREATING DEPRESSION AND/OR REDUCING A RISK ASSOCIATEDWITH DEVELOPING DEPRESSION AND RELATED CONDITIONS

Disclosed herein are several embodiments of methods directed to treatingan incidence of depression in a patient using catheter-based renalneuromodulation. Further embodiments disclosed herein are directed topreventing an incidence of depression and/or other conditions associatedwith an increased risk of developing depression in a patient usingcatheter-based renal neuromodulation. The methods disclosed herein mayrepresent various advantages over a number of conventional approachesand techniques in that they allow for the potential targeting ofelevated sympathetic drive, which may either be a cause of severalneurological, immune vascular, or other physiological risk factorsassociated with depression or a key mediator of the disordermanifestation. Also, the disclosed methods provide for localizedtreatment and limited duration treatment regimens (e.g., one-timetreatment), thereby reducing patient long-term treatment complianceissues.

In certain embodiments, the methods provided herein comprise performingrenal neuromodulation, thereby decreasing sympathetic renal nerveactivity, for example, for the purposes of being able to provide one ormore of a reduction in a number of depression risk factors, a reductionin severity of one or more depression risk factors, a reduction in acalculated depression risk score, a reversal in vascular damagefacilitated by sympathetic activity, or a reduction in systemicinflammation. For example, renal neuromodulation is expected to reduce alevel of central sympathetic activity that may contribute to one moreunderlying causes of depression.

Renal neuromodulation may be repeated one or more times at variousintervals until a desired sympathetic nerve activity level or anothertherapeutic benchmark is reached. In one embodiment, for example, adecrease in sympathetic nerve activity may be observed via a marker ofsympathetic nerve activity in patients, such as decreased levels ofplasma norepinephrine (noradrenaline), changes in levels of systemicrenin in plasma, changes in levels of angiotensin II in plasma, and/orchanges in levels of systemic aldosterone in plasma. Other measures ormarkers of sympathetic nerve activity can include MSNA, norepinephrinespillover, and/or heart rate variability. In some instances, a decreasein SNS activity can be observed as a decrease in norepinephrine andmetabolites thereof (e.g., vanillomandelic acid (VMA)) in urine. Inanother embodiment, other measurable physiological parameters ormarkers, such as improved baroreceptor sensitivity, improved heart rateresponses to stimuli/stress, improved heart rate variability, improvedskin conductance, improved blood pressure control (e.g., lower bloodpressure), improved blood pressure variability (e.g., improved MSBP,improved nocturnal blood pressure “dipping”), lower levels of peripheralinflammatory biomarkers (e.g., IL-6, IL-1β, IL-2, TNF-α, CRP, etc.),improved levels of NPY, reduced cortisol levels, reduced CAR, reducedglucocorticoid resistance, improved brain neural activity (e.g., in thehippocampus and other brain regions), cessation or reversal of brainatrophy (e.g., in the hippocampus), changes in aldosterone-to-reninratio (ARR), changes in a salt suppression test, changes in blood plasmalevels of potassium, improved blood glucose regulation, etc., can beused to assess efficacy of the thermal modulation treatment for patientsdiagnosed as having depression or for patients having one or more riskfactors for developing depression, and/or having a calculated depressionrisk score above a threshold depression risk score. In certainembodiments, renal neuromodulation may be repeated one or more times atvarious intervals until a desired sympathetic nerve activity level oranother therapeutic benchmark is reached for such patients.

In certain embodiments of the methods provided herein, renalneuromodulation is expected to result in a change in sympathetic nerveactivity and/or in other measurable physiological parameters or markers,over a specific timeframe. For example, in certain of these embodiments,sympathetic nerve activity levels are decreased over an extendedtimeframe, e.g., within 1 month, 2 months, 3 months, 6 months, 9 monthsor 12 months post-neuromodulation.

In several embodiments, the methods disclosed herein may comprise anadditional step of measuring sympathetic nerve activity levels, and incertain of these embodiments, the methods can further comprise comparingthe activity level to a baseline activity level. Such comparisons can beused to monitor therapeutic efficacy and to determine when and if torepeat the neuromodulation procedure. In certain embodiments, a baselinesympathetic nerve activity level is derived from the subject undergoingtreatment. For example, baseline sympathetic nerve activity level may bemeasured in the subject at one or more timepoints prior to treatment. Abaseline sympathetic nerve activity value may represent sympatheticnerve activity at a specific timepoint before neuromodulation, or it mayrepresent an average activity level at two or more timepoints prior toneuromodulation. In certain embodiments, the baseline value is based onsympathetic nerve activity immediately prior to treatment (e.g., afterthe subject has already been catheterized). Alternatively, a baselinevalue may be derived from a standard value for sympathetic nerveactivity observed across the population as a whole or across aparticular subpopulation. In certain embodiments, post-neuromodulationsympathetic nerve activity levels are measured in extended timeframespost-neuromodulation, e.g., 3 months, 6 months, 12 months or 24 monthspost-neuromodulation.

In certain embodiments of the methods provided herein, the methods aredesigned to decrease sympathetic nerve activity to a target level. Inthese embodiments, the methods include a step of measuring sympatheticnerve activity levels post-neuromodulation (e.g., 6 monthspost-treatment, 12 months post-treatment, etc.) and comparing theresultant activity level to a baseline activity level as discussedabove. In certain of these embodiments, the treatment is repeated untilthe target sympathetic nerve activity level is reached. In otherembodiments, the methods are simply designed to decrease sympatheticnerve activity below a baseline level without requiring a particulartarget activity level.

In one embodiment, measured norepinephrine content (e.g., assessed viatissue biopsy, assessed in real-time via intravascular blood collectiontechniques, assessed in real-time via urine, etc.) can be reduced (e.g.,at least about 5%, 10%, 20% or by at least 40%) in the patient within,for example, about three months after at least partially inhibitingsympathetic neural activity in nerves proximate a renal blood vessel.

In one embodiment, renal neuromodulation may be performed on a patienthaving one or more risk factors or symptoms associated with depressionto improve the physiological state of at least one of the depressionrisk factors. In some embodiments, for example, renal neuromodulationmay result in a reduction in a patient's heart rate under stress, mayraise heart rate variability, lower a MSBP, lower a nocturnal bloodpressure level, reduce systolic blood pressure, reduce blood pressurevariability, increase baroreceptor sensitivity, lower skin conductance,reduce a serum level of an inflammatory biomarker, or reduce a level ofinsulin resistance. In a particular example, a patient having depressionand decreased heart rate variability (e.g., SDNN<50 ms) may have heartrate variability within a normal range (e.g., SDNN>50 ms) after aneuromodulation procedure. In a further example, a reduction in MSBP canbe, for example, by at least about 5%, 10% or a greater amount asdetermined by average ambulatory blood pressure analysis before andafter (e.g., 1, 3, 6, or 12 months after) a renal neuromodulationprocedure. Likewise, and in yet a further example, a reduction innocturnal blood pressure level can be, for example, by at least about5%, 10%, or a greater amount as determined by average ambulatory bloodpressure analysis before and after (e.g., 1, 3, 6, or 12 months after) arenal neuromodulation procedure.

In the case of systemic inflammation and/or a patient having elevatedserum levels of inflammatory biomarkers, IL-6, IL-1β, IL-2, TNF-α and/orCRP, renal neuromodulation may improve (e.g., reduce a level of) markersof inflammation (e.g., IL-6, IL-1β, IL-2, TNF-α, CRP), and in someembodiments, provide a reduction in biomarker level, for example, byabout 5%, 10%, 25%, 45% or a greater amount as determined by bloodanalysis before and after (e.g., 1, 3, 6, or 12 months after) a renalneuromodulation procedure. In an example where the patient has elevatedcortisol levels, elevated CRH levels, and/or glucocorticoid resistance,renal neuromodulation may improve (e.g., reduce a level of) cortisollevels, CRH levels, and/or glucocorticoid resistance by about 5%, about10%, about 20% or greater amount as determined by quantitative analysis(e.g., dexamethasone binding assay, dexamethasone suppression test,radioimmunoassay, CRH stimulation test, etc.). In other embodiments, andin particular afflicted patients, renal neuromodulation may increasearteriole blood flow, reduce a level of atherosclerosis, or reduce adegree of arterial stiffening in the patient by about 5%, 10% or agreater amount as determined by qualitative or quantitative analysis(e.g., computerized tomography (CT) scan, pulse wave velocity (PWV)analysis, angiography, etc.) before and after (e.g., 1, 3, 6, or 12months after) a renal neuromodulation procedure.

In another embodiment, renal neuromodulation may be performed on apatient having a calculated depression risk score associated with adepression status in the patient that is above a threshold depressionrisk score. Renal neuromodulation is expected to therapeutically improvethe patient's depression risk score and thereby reduce, diminish,reverse or eliminate the depression disorder in the patient. In oneembodiment, a threshold depression risk score may be a theoretical riskscore (e.g., based on population studies) that represents a cut-offscore for a depression diagnosis. In other embodiments, the thresholddepression risk score may be a theoretical risk score that represents anupper limit of acceptable severity and/or acceptable risk of developingdepression.

In a particular example, a patient may be assessed for a number offactors that have been previously determined to validate a depressiondiagnosis and/or to carry risk for the development of depression (e.g.,number or severity of core depression symptoms, genetic/epigeneticfactors, presence of sleep disturbances, number or duration of adverselife events or circumstances the patient has experienced, number ofprior traumatic events the patient experienced, presence of abuse orneglect during childhood, gender, marital status, presence of personalor family history of depression or mental illness, absence of familyand/or social support, low heart rate variability, elevated cortisollevels, elevated CAR, low NPY levels, baroreceptor sensitivity, bloodpressure, MSBP levels, nocturnal blood pressure levels, MSNA levels,body mass index, substance abuse/habits, etc.). Using a depression riskscore calculator tool (e.g., based on epidemiological data), a patient'srisk score can be assessed. For patients having a calculated depressionrisk score above the threshold depression risk score (e.g., signifyingan undesirable level of depression severity or probability of havingdepression), a renal neuromodulation procedure is performed. Renalneuromodulation may improve (e.g., lower, reverse, reduce a rate ofincrease over time, etc.) the patient's depression risk score. Forexample, following a renal neuromodulation procedure, a patient'scalculated depression risk score may reduce (e.g., improve) by about byabout 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about40%, about 50%, about 75%, or a greater amount as determined by thedepression risk score calculator tool. Such improvements in a patient'sdepression risk score may be detected, for example 1, 3, 6, 12, or 24months after a renal neuromodulation procedure. In certain embodiments,a threshold risk score can be variable depending on a number of factorsincluding gender, age, socioeconomic levels, geographical residence,etc. For example, a threshold risk score for a male patient can begreater than a threshold risk score for a female patient.

In addition to (or instead of) affecting one or more measurable riskfactors associated with depression or the development of depression,renal neuromodulation may efficaciously treat one or more measurablephysiological parameter(s) or sequela(e) corresponding to theprogression or severity of depression in the patient. For example, insome embodiments, renal neuromodulation may result in an improvement(e.g., prevent further decline, maintain, or improve) in a patient'scognitive abilities and/or emotional/social functioning abilities asassessed by one or more accepted diagnostic test methods (e.g.,screening tools, questionnaires, etc.) for identifying depression risk,severity and diagnosis (e.g., MDI, PHQ-9, MINI, HAM-D₁₇, MES, Zung-SDS,BDI-II, VAS, FPA, etc.). In a specific embodiment, a patient may improvea depression screening test score, maintain a depression screening testscore, or decrease a rate of decline (e.g., rate of depression disorderprogression) in a test score over time following a renal neuromodulationprocedure. Such improvements in a patient's cognitive abilities and/oremotional/social functioning abilities may be detected, for example 1,3, 6, or 12 months after a renal neuromodulation procedure. In otherembodiments, improvements are detected 2, 3, 4, 5 or 10 years after arenal neuromodulation procedure. In some embodiments, a depressiondiagnostic test score can be improved by about 5%, about 10%, about 15%,about 20%, about 30%, about 40%, about 50%, or about 75%. In otherembodiments, patients may report that daily activities are easierfollowing a neuromodulation procedure.

In another example, renal neuromodulation may efficaciously treat one ormore aspects of sleep disturbance associated with depression in thepatient. For example, a patient may have an improvement (e.g., areduction) in the number, the type and/or the duration of sleepdisturbances (e.g., number of nights of difficulty falling asleep,number of nights difficulty maintaining or staying asleep, duration oftime it takes to fall asleep, duration of night awake, number of timespatient wakes up during the night, etc.) following a renalneuromodulation procedure. Such improvements in a patient's sleeppatterns and/or sleep quality may be detected, for example 1, 3, 6, or12 months after a renal neuromodulation procedure. In other embodiments,improvements are detected 2 or 3 years after a renal neuromodulationprocedure. In some embodiments, the patient's sleep quality (e.g.,number of nights with sleep disturbance, time duration of sleepdisturbance, etc.) can be improved by about 5%, about 10%, about 15%,about 20%, about 30%, about 40%, about 50%, or about 75% within 3 to 12months or within 3 to 6 months following a renal neuromodulationprocedure.

In a further example, renal neuromodulation may efficaciously treat oneor more aspects of depression-related symptoms in the patient. Forexample, a patient may have an improvement (e.g., a reduction) in thenumber, the type, and/or the severity of depression-related symptoms(e.g., feeling depressed or down most days or nearly every day, feelingsof sadness, apathy, mood swings, loss of interest or pleasure inactivities, guilt, anxiety, insomnia, restless sleep, excess sleepiness,fatigue, excessive hunger, loss of appetite, irritability, excessivecrying, lack of concentration, slowness in activity and/or thoughts ofsuicide) following a renal neuromodulation procedure. Such improvementsin a patient's depression-related symptoms may be detected, for example,1, 3, 6, or 12 months after a renal neuromodulation procedure. In otherembodiments, improvements are detected 2 or 3 years after a renalneuromodulation procedure. In some embodiments, the level ofdepression-related symptoms (e.g., level of severity, number ofdepression-related symptoms, the number of days the patient experiencesdepression-related symptoms within a logged time period, etc.) can beimproved by about 5%, about 10%, about 15%, about 20%, about 30%, about40%, about 50%, or about 75% within, for example, 3 to 12 months orwithin 3 to 6 months following a renal neuromodulation procedure. Insome embodiments, the patient can experience complete regression or fullrecovery from the depression-related symptoms.

Renal neuromodulation may prevent or reduce an incidence of developingone or more comorbid conditions or diseases in a patient withdepression. For example a patient with depression treated with renalneuromodulation may have a decreased likelihood of developingpre-hypertension, hypertension, cardiovascular disease, stroke risk,metabolic disorders, insulin resistance, diabetes, systemicinflammation, etc. In another embodiment, patients with depressionhaving one or more comorbid conditions or diseases may have animprovement in (e.g., reduction, maintain a level, slow a rate ofprogression of) in the one or more comorbid conditions or diseases andassociated symptoms thereof. In a particular example, a pre-hypertensivepatient (e.g., systolic BP of 120-139 mmHg/diastolic BP of 80-89 mmHg)may have blood pressure below the pre-hypertensive range after a renalneuromodulation procedure. Likewise, a hypertensive patient (e.g.,systolic BP>140 mmHg/diastolic BP>90 mmHg) may have blood pressure belowthe hypertensive range after a renal neuromodulation procedure.Corresponding results may be obtained with angiotensin II levels, plasmaaldosterone concentration, plasma renin activity, and/oraldosterone-to-renin ratio. For example, a reduction in analdosterone-to-renin ratio can be, for example, by at least about 5%,10% or a greater amount (e.g., about 50%, about 80%, about 90%) asdetermined by blood analysis and calculation before and after (e.g., 1,3, 6, or 12 months after) a renal neuromodulation procedure.

Other measurable physiological parameters may also improve followingrenal neuromodulation. For example, a patient may have an improvement in(e.g., reduction, maintain a level of, slow a rate of progression of)atherosclerosis of extracranial and/or intracranial arteries, clinicalmeasurements of aortic and large-artery, small-vessel disease or otheralterations in small arteries providing physiological blood flow, neuralactivity (e.g., in the amygdala, ventromedial prefrontal cortex, dorsalanterior cingulate cortex, hippocampus and/or insular cortex or otherregions involved in the limbic system), and cerebral atrophy (e.g.,hippocampal volume reduction), following a renal neuromodulationprocedure as determined by qualitative or quantitative analysis (e.g.,CT scan, PWV analysis, angiography, MM, PET scan, etc.) before and after(e.g., 1, 3, 6, or 12 months after; 2, 3, 4, 5 or 10 years after) arenal neuromodulation procedure. In a particular example, hippocampalvolume can be increased (e.g., hippocampal growth) at least about 5%,about 10%, about 15%, about 20%, about 30%, or a greater amount in thepatient within about three months to about 12 months after at leastpartially inhibiting sympathetic neural activity in nerves proximate arenal artery of the kidney.

As discussed previously, the development of depression in certainindividuals may be related to sympathetic overactivity either before(e.g., chronic or episodic), during (e.g., at the time of), or followingan adverse life event or circumstance, and, correspondingly, the degreeof sympathoexcitation in a patient may be related to one or more of theseverity of the clinical presentation of depression, the number oftraumatic events experienced by the patient, whether the patient has hadadversity during childhood, number and duration of adverse life eventsor circumstances (e.g., triggering psychological stress responses),personal or family history of depression or mental illness, history ofcardiovascular disease or stroke, among other psychological,physiological and genetic/epigenetic factors. The kidneys are positionedto be both a cause (via afferent nerve fibers) and a target (viaefferent sympathetic nerves) of elevated central sympathetic drive. Insome embodiments, renal neuromodulation can be used to reduce centralsympathetic drive in a patient demonstrating one or more risk factorsfor depression in a manner that treats the patient for depression and/orto prevent an incidence of depression in the patient in later life. Insome embodiments, for example, MSNA can be reduced by at least about 10%in the patient within about three months after at least partiallyinhibiting sympathetic neural activity in nerves proximate a renalartery of the kidney. Similarly, in some instances whole bodynorepinephrine spillover to plasma can be reduced at least about 20%,about 30%, about 40%, about 45%, about 50% or a greater amount in thepatient within about three months to about 12 months after at leastpartially inhibiting sympathetic neural activity in nerves proximate arenal artery of the kidney. Additionally, measured norepinephrinecontent (e.g., assessed via renal biopsy, assessed in real-time viaintravascular blood collection techniques, assessed in real-time viaurine, etc.) can be reduced (e.g., at least about 5%, 10%, or by atleast 20%) in the patient within about three months after at leastpartially inhibiting sympathetic neural activity in nerves proximate arenal artery innervating the kidney.

In one prophetic example, a patient having one or more suspected riskfactors for depression and/or the development of depression can besubjected to a baseline assessment indicating a first set of measurableparameters corresponding to the one or more risk factors. Suchparameters can include, for example, levels of central sympathetic drive(e.g., MSNA, whole body norepinephrine spillover), measurednorepinephrine content (e.g., assessed via tissue biopsy, plasma orurine), blood pressure, 24-hour blood pressure variability, heart ratevariability, baroreceptor sensitivity, heart rate during stress/stimuli,skin conductance, glucocorticoid levels (e.g., in hair, urine, plasma,etc.), glucocorticoid resistance, CAR level, NPY level, CRH level,inflammatory biomarker levels (e.g., IL-6, CRP, etc.), cholesterollevels, blood glucose levels, fasting blood insulin levels, measures ofinsulin sensitivity, body mass index, perceived cognitive functioninglevel (e.g., self-reporting, third-party reporting, etc.), one or morebrain function test scores, and brain/body imaging for vascularremodeling (e.g., arteriole stiffness, arterial blood flow) and/or brainstructural alterations (e.g., atrophy, neural activity, etc.). Followingbaseline assessment, the patient can be subjected to a renalneuromodulation procedure. Such a procedure can, for example, includeany of the treatment modalities described herein or another treatmentmodality in accordance with the present technology. The treatment can beperformed on nerves proximate one or both kidneys of the patient.Following the treatment (e.g., 1, 3, 6, or 12 months following thetreatment; 2, 3, 4, 5 or 10 years following the treatment), the patientcan be subjected to a follow-up assessment. The follow-up assessment canindicate a measurable improvement in one or more physiologicalparameters corresponding to the one or more suspected risk factors fordepression or the development of depression.

The methods described herein address the sympathetic excess that isthought to be an underlying factor in depression progression or acentral mechanism through which multiple depression risk factors aremanifest in patients. Currently, there are no therapies prescribed toaddress the effects of sympathetic excess in patients suspected ofhaving depression or a risk of developing depression. Certain proposedtherapies, such as lifestyle alterations (e.g., exercise, diet, etc.),cognitive behavioral therapy, blood pressure maintenance (e.g.,administration of anti-hypertensive therapies), anti-depression and/oranti-anxiety medications, and reduction and/or maintenance ofcholesterol have significant limitations including limited efficacy,undesirable side effects and may be subject to adverse or undesirabledrug interactions when used in combination. Moreover, use of any drugregimens (e.g., antidepressant, anti-anxiety, anti-hypertensive,cholesterol-lowering, anti-inflammatory, etc.) can have many challenges,including drug contraindications and drug adherence (particularly priorto onset of symptoms). For example, many of these drug regimens mayrequire the patient to remain compliant with the treatment regimenstarting in early life (e.g., prior to on-set of depression diagnosis)and continue compliance over time. In contrast, neuromodulation can be aone-time or otherwise limited treatment that would be expected to havedurable benefits to treat depression, reduce severity of depressionand/or inhibit the long-term potential of developing depression andthereby achieve a favorable patient outcome.

In some embodiments, patients demonstrating one or more risk factorsassociated with depression or the development of depression and/or haveone or more physiological indicators of sympathetic excess (e.g.,combined with additional risk factors) can be treated with renalneuromodulation alone. However, in other embodiments, combinations oftherapies can be tailored based on specific conditions and depressionrisk factors in a particular patient. For example, certain patients canbe treated with combinations of therapies such as one or moreconventional therapies for treating depression or anxiety, for treatingsleep disorders, and/or reducing blood pressure (e.g., anti-hypertensivedrug(s)) and treated with one or more neuromodulation treatments. Inanother example, renal neuromodulation can be combined with cholesterollowering agents (e.g., statins), anti-inflammatory therapy (e.g.,drug(s)), as well as weight loss and lifestyle changerecommendations/programs. In certain embodiments, a patient beingtreated with one or more pharmaceutical drugs for depression and/orconditions associated with depression can be treated with renalneuromodulation to reduce at least one of number of or a measured dosageof the pharmaceutical drugs administered to the patient.

Treatment of depression risk factors or symptoms and conditionsassociated with depression may refer to preventing the condition,slowing the onset or rate of development of the condition, reducing therisk of developing the condition, preventing or delaying the developmentof symptoms associated with the condition, reducing or ending symptomsassociated with the condition, generating a complete or partialregression of the condition, or some combination thereof.

IV. SELECTED EXAMPLES OF NEUROMODULATION MODALITIES

As noted previously, complete or partial neuromodulation of a targetrenal sympathetic nerve in accordance with embodiments of the presenttechnology can be electrically-induced, thermally-induced,chemically-induced, or induced in another suitable manner or combinationof manners at one or more suitable locations along one or more renalblood vessels during a treatment procedure. For example, neuromodulationmay be achieved using various modalities, including for examplemonopolar or bipolar RF energy, pulsed RF energy, microwave energy,laser light or optical energy, magnetic energy, ultrasound energy (e.g.,intravascularly delivered ultrasound, extracorporeal ultrasound,high-intensity focused ultrasound (HIFU)), direct heat energy, radiation(e.g., infrared, visible, gamma), or cryotherapeutic energy, chemicals(e.g., drugs or other agents), or combinations thereof. Where a systemuses a monopolar configuration, a return electrode or ground patch fixedexternally on the subject can be used. In certain embodiments,neuromodulation may utilize one or more devices including, for example,catheter devices such as the Symplicity™ catheter (Medtronic, Inc.).Other suitable thermal devices are described in U.S. Pat. Nos.7,653,438, 8,347,891, and U.S. patent application Ser. No. 13/279,205,filed Oct. 21, 2011. Other suitable devices and technologies aredescribed in U.S. patent application Ser. No. 13/279,330, filed Oct. 23,2011, International Patent Application No. PCT/US2015/021835, filed Mar.20, 2015, and International Patent Application No. PCT/US2015/013029,filed Jan. 27, 2015. Further, electrodes (or other energy deliveryelements) can be used alone or with other electrodes in amulti-electrode array. Examples of suitable multi-electrode devices aredescribed in U.S. patent application Ser. No. 13/281,360, filed Oct. 25,2011, and U.S. Pat. No. 8,888,773. Other examples of suitable directheat devices are described in International Patent Application No.PCT/US2014/023738 filed Mar. 11, 2014, and U.S. patent application Ser.No. 14/203,933, filed Mar. 11, 2014. All of the foregoing patentreferences are incorporated herein by reference in their entireties.

In those embodiments of the methods disclosed herein that utilizepartial ablation, the level of energy delivered to the target artery andsurrounding tissue may be different than the level that is normallydelivered for complete neuromodulation. For example, partialneuromodulation using RF energy may use alternate algorithms ordifferent power levels than RF energy for complete neuromodulation.Alternatively, partial neuromodulation methods may utilize the samelevel of energy, but delivered to a different depth within the tissue orto a more limited area. In certain embodiments, partial neuromodulationmay be achieved using a device that differs from a device used forcomplete neuromodulation. In certain embodiments, a particular treatmentor energy modality may be more suitable for partial neuromodulation thanother treatment or energy modalities. In some embodiments,neuromodulation may be achieved using one or more chemical agents, suchas by drug delivery. In those embodiments that utilize partialneuromodulation, the methods may utilize the same devices and/or drugdelivery systems used for complete neuromodulation, or they may usecompletely different devices for energy and/or drug delivery.

Thermal effects can include both thermal ablation and non-ablativethermal alteration or damage (e.g., via sustained heating and/orresistive heating) to partially or completely disrupt the ability of anerve to transmit a signal. Such thermal effects can include the heatingeffects associated with electrode-based or transducer-based treatment.For example, a treatment procedure can include raising the temperatureof target neural fibers to a target temperature above a first thresholdto achieve non-ablative alteration, or above a second, higher thresholdto achieve ablation. In some embodiments, the target temperature can behigher than about body temperature (e.g., about 37° C.) but less thanabout 45° C. for non-ablative alteration, and the target temperature canbe higher than about 45° C. for ablation. More specifically, heatingtissue to a temperature between about body temperature and about 45° C.can induce non-ablative alteration, for example, via moderate heating oftarget neural fibers or vascular/luminal structures that perfuse thetarget neural fibers. In cases where vascular structures are affected,the target neural fibers can be denied perfusion resulting in necrosisof the neural tissue. For example, this may induce non-ablative thermalalteration in the fibers or structures. Heating tissue to a targettemperature higher than about 45° C. (e.g., higher than about 60° C.)can induce ablation, for example, via substantial heating of targetneural fibers or of vascular or luminal structures that perfuse thetarget fibers. In some patients, it can be desirable to heat tissue totemperatures that are sufficient to ablate the target neural fibers orthe vascular or luminal structures, but that are less than about 90° C.,e.g., less than about 85° C., less than about 80° C., or less than about75° C. Other embodiments can include heating tissue to a variety ofother suitable temperatures.

In some embodiments, complete or partial neuromodulation of a renalsympathetic nerve can include an electrode-based or transducer-basedtreatment modality alone or in combination with another treatmentmodality. Electrode-based or transducer-based treatment can includedelivering electricity and/or another form of energy to tissue at atreatment location to stimulate and/or heat the tissue in a manner thatmodulates neural function. For example, sufficiently stimulating and/orheating at least a portion of a sympathetic nerve can slow orpotentially block conduction of neural signals to produce a prolonged orpermanent reduction in sympathetic activity. A variety of suitable typesof energy, such as those mentioned above, can be used to stimulateand/or heat tissue at a treatment location. In some embodiments,neuromodulation can be conducted in conjunction with one or more othertissue modulation procedures. An element, transducer, or electrode usedto deliver this energy can be used alone or with other elements,transducers, or electrodes in a multi-element array. Furthermore, theenergy can be applied from within the body (e.g., within the vasculatureor other body lumens in a catheter-based approach or outside thevasculature using, for example, a Natural Orifice TransluminalEndoscopic Surgery or NOTES procedure) and/or from outside the body,e.g., via an applicator positioned outside the body. In someembodiments, energy can be used to reduce damage to non-targeted tissuewhen targeted tissue adjacent to the non-targeted tissue is subjected toneuromodulating cooling.

As an alternative to or in conjunction with electrode-based ortransducer-based approaches, other suitable energy delivery techniques,such as a cryotherapeutic treatment modality, can be used for achievingtherapeutically-effective neuromodulation of a target sympathetic nerve.For example, cryotherapeutic treatment can include cooling tissue at atreatment location in a manner that modulates neural function. Forexample, sufficiently cooling at least a portion of a target sympatheticnerve can slow or potentially block conduction of neural signals toproduce a prolonged or permanent reduction in sympathetic activityassociated with the target sympathetic nerve. This effect can occur as aresult of cryotherapeutic tissue damage, which can include, for example,direct cell injury (e.g., necrosis), vascular or luminal injury (e.g.,starving cells from nutrients by damaging supplying blood vessels),and/or sublethal hypothermia with subsequent apoptosis. Exposure tocryotherapeutic cooling can cause acute cell death (e.g., immediatelyafter exposure) and/or delayed cell death, e.g., during tissue thawingand subsequent hyperperfusion.

Neuromodulation using a cryotherapeutic treatment in accordance withembodiments of the present technology can include cooling a structureproximate an inner surface of a vessel or chamber wall such that tissueis effectively cooled to a depth where sympathetic nerves reside. Forexample, a cooling assembly of a cryotherapeutic device can be cooled tothe extent that it causes therapeutically-effective, cryogenicneuromodulation. In some embodiments, a cryotherapeutic treatmentmodality can include cooling that is not configured to causeneuromodulation. For example, the cooling can be at or above cryogenictemperatures and can be used to control neuromodulation via anothertreatment modality, e.g., to protect tissue from neuromodulating energy.Other suitable cryotherapeutic devices are described, for example, inU.S. patent application Ser. No. 13/279,330, filed Oct. 23, 2011, andincorporated herein by reference in its entirety.

Cryotherapeutic treatment can be beneficial in certain embodiments. Forexample, rapidly cooling tissue can provide an analgesic effect suchthat cryotherapeutic treatment can be less painful than other treatmentmodalities. Neuromodulation using cryotherapeutic treatment cantherefore require less analgesic medication to maintain patient comfortduring a treatment procedure compared to neuromodulation using othertreatment modalities. Additionally, reducing pain can reduce patientmovement and thereby increase operator success and/or reduce proceduralcomplications. Cryogenic cooling also typically does not causesignificant collagen tightening, and therefore is not typicallyassociated with vessel stenosis. In some embodiments, cryotherapeutictreatment can include cooling at temperatures that can cause therapeuticelements to adhere to moist tissue. This can be beneficial because itcan promote stable, consistent, and continued contact during treatment.The typical conditions of treatment can make this an attractive featurebecause, for example, patients can move during treatment, cathetersassociated with therapeutic elements can move, and/or respiration cancause organs and tissues to rise and fall and thereby move the arteriesand other structures associated with these organs and tissues. Inaddition, blood flow is pulsatile and can cause structures associatedwith the kidneys to pulse. Cryogenic adhesion also can facilitateintravascular or intraluminal positioning, particularly inrelatively-small structures (e.g., renal branch arteries) in whichstable intravascular or intraluminal positioning can be difficult toachieve.

The use of ultrasound energy can be beneficial in certain embodiments.Focused ultrasound is an example of a transducer-based treatmentmodality that can be delivered from outside the body (i.e.,extracorporeal). In some embodiments, focused ultrasound treatment canbe performed in close association with imaging, e.g., magneticresonance, computed tomography, fluoroscopy, ultrasound (e.g.,intravascular or intraluminal), optical coherence tomography, or anothersuitable imaging modality. For example, imaging can be used to identifyan anatomical position of a treatment location, e.g., as a set ofcoordinates relative to a reference point. The coordinates can then beentered into a focused ultrasound device configured to change thedistance from source to target, power, angle, phase, or other suitableparameters to generate an ultrasound focal zone at the locationcorresponding to the coordinates. In some embodiments, the focal zonecan be small enough to localize therapeutically-effective heating at thetreatment location while partially or fully avoiding potentially harmfuldisruption of nearby structures. To generate the focal zone, theultrasound device can be configured to pass ultrasound energy through alens, and/or the ultrasound energy can be generated by a curvedtransducer or by multiple transducers in a phased array (curved orstraight). In certain embodiments, the ultrasound device may be acatheter device with an ultrasound transducer or an array of ultrasoundtransducers on its distal tip. In other embodiments the ultrasounddevice may comprise a cylindrical transducer. In certain embodimentswherein the ultrasound device is being used to perform partial ablation,the device may include discrete and/or forward-facing transducers thatcan be rotated and inserted at specific conditions, thereby allowing formore discrete lesion formation. In other embodiments, however, theextracorporeal and/or intravascular ultrasound devices may havedifferent arrangements and/or different features.

In some embodiments, neuromodulation can be effected using achemical-based treatment modality alone or in combination with anothertreatment modality. Neuromodulation using chemical-based treatment caninclude delivering one or more chemicals (e.g., drugs or other agents)to tissue at a treatment location in a manner that modulates neuralfunction. The chemical, for example, can be selected to affect thetreatment location generally or to selectively affect some structures atthe treatment location over other structures. In some embodiments, thechemical can be guanethidine, vincristine, ethanol, phenol, aneurotoxin, or another suitable agent selected to alter, damage, ordisrupt nerves. In some embodiments, energy (e.g., light, ultrasound, oranother suitable type of energy) can be used to activate the chemicaland/or to cause the chemical to become more bioavailable. A variety ofsuitable techniques can be used to deliver chemicals to tissue at atreatment location. For example, chemicals can be delivered via one ormore needles originating outside the body or within the vasculature orother body lumens (see, e.g., U.S. Pat. No. 6,978,174, the disclosure ofwhich is hereby incorporated by reference in its entirety). In anintravascular example, a catheter can be used to intravascularlyposition a therapeutic element including a plurality of needles (e.g.,micro-needles) that can be retracted or otherwise blocked prior todeployment. In other embodiments, a chemical can be introduced intotissue at a treatment location via simple diffusion through a vesselwall, electrophoresis, or another suitable mechanism. Similar techniquescan be used to introduce chemicals that are not configured to causeneuromodulation, but rather to facilitate neuromodulation via anothertreatment modality. Examples of such chemicals include, but are notlimited to, anesthetic agents and contrast agents.

Renal neuromodulation in conjunction with the methods and devicesdisclosed herein may be carried out at a location proximate (e.g., at ornear) a vessel or chamber wall (e.g., a wall of a renal artery, one ormore branch vessels from the renal artery, a ureter, a renal pelvis, amajor renal calyx, a minor renal calyx, and/or another suitablestructure), and the treated tissue can include tissue proximate thetreatment location. For example, with regard to a renal artery, atreatment procedure can include modulating nerves in the renal plexus,which lay intimately within or adjacent to the adventitia of the renalartery.

In certain embodiments, monitoring, assessing and/or determiningneuromodulation efficacy can be accomplished by detecting changes in thelevel of one or more surrogate biomarkers (e.g., a biomarker thatdirectly or indirectly correlates with sympathetic nerve activity in thepatient, a biomarker that directly or indirectly correlates withhypertension, arterial stiffness and/or an inflammatory response in thepatient) in serum, plasma and/or urine in response to neuromodulation.Systems and method for monitoring the efficacy of neuromodulation bymeasuring the levels of one or more biomarkers associated withneuromodulation including, for example, proteins or non-proteinmolecules that exhibit an increase or decrease in level or activity inresponse to neuromodulation are described in, e.g., International PatentApplication No. PCT/US2013/030041, filed Mar. 8, 2013, and InternationalPatent Application No. PCT/US2015/047568, filed Aug. 28, 2015, thedisclosures of which are incorporated herein by reference in theirentireties. In other embodiments, measured levels of protein ornon-protein molecules (e.g., associated with norepinephrine spillover,associated with inflammatory responses, etc.) that exhibit an increaseor decrease in level or activity in response to targeted neuromodulationcan be assessed pre- and post-neuromodulation in tissue biopsies.

V. SELECTED EMBODIMENTS OF RENAL NEUROMODULATION SYSTEMS AND DEVICES

FIG. 4 illustrates a renal neuromodulation system 10 configured inaccordance with an embodiment of the present technology. The system 10,for example, may be used to perform therapeutically-effective renalneuromodulation on a patient (a) to reduce the risk of occurrence ofdepression, (b) to reduce a calculated depression risk scorecorresponding to a depression status, (c) to reduce a severity ofneurological symptoms relating to depression, and/or (d) to treat and/orprevent development of one or more comorbid conditions/diseasesassociated with depression (e.g., hypertension, cardiovascular disease,stroke risk, metabolic disorders, insulin resistance, diabetes, systemicinflammation, etc.). In one embodiment, the patient may be diagnosedwith increased overall sympathetic activity, and, in particular,conditions associated with central sympathetic overstimulation andincreased risk of developing depression, such as hypertension, bloodpressure variability, systemic inflammation, sleep disorders, anxietyand panic disorders, cardiovascular disease, history of stroke or TIA,obesity, metabolic syndrome, insulin resistance and diabetes, amongothers.

The system 10 includes an intravascular treatment device 12 operablycoupled to an energy source or console 26 (e.g., a RF energy generator,a cryotherapy console). In the embodiment shown in FIG. 4, the treatmentdevice 12 (e.g., a catheter) includes an elongated shaft 16 having aproximal portion 18, a handle 34 at a proximal region of the proximalportion 18, and a distal portion 20 extending distally relative to theproximal portion 18. The treatment device 12 further includes aneuromodulation assembly or treatment section 21 at the distal portion20 of the shaft 16. The neuromodulation assembly 21 can be configured toablate nerve tissue and/or for monitoring one or more physiologicalparameters within the vasculature. Accordingly, a neuromodulationassembly 21 suitable for ablation may include one or more electrodes,transducers, energy-delivery elements or cryotherapeutic coolingassemblies. Neuromodulation assemblies 21 suitable for monitoring mayalso include a nerve monitoring device and/or blood collection/analysisdevice. In some embodiments, the neuromodulation assembly 21 can beconfigured to be delivered to a renal blood vessel (e.g., a renalartery) in a low-profile configuration.

In one embodiment, for example, the neuromodulation assembly 21 caninclude a single electrode. In other embodiments, the neuromodulationassembly 21 may comprise a basket and a plurality of electrodes carriedby the basket. The electrodes on the basket may be spaced apart fromeach other such that each electrode is approximately 90° apart from aneighboring electrode. In yet another embodiment, the neuromodulationassembly 21 can include a balloon and a plurality of bipolar electrodescarried by the balloon. In still another embodiment, the neuromodulationassembly 21 has a plurality of electrodes arranged along an elongatedmember transformable between a low-profile, delivery configuration(e.g., contained in a delivery catheter) and an expanded, deployedconfiguration in which the elongated member has a helical/spiral shape.In further embodiments, the neuromodulation assembly 21 can include oneor more electrodes configured to deliver ablation energy and/orstimulation energy. In some arrangements, the neuromodulation assembly21 can include one or more sensor(s) for detecting impedance or nervemonitoring signals. In any of the foregoing embodiments, theneuromodulation assembly 21 may comprise an irrigated electrode.

Upon delivery to a target treatment site within a renal blood vessel,the neuromodulation assembly 21 can be further configured to be deployedinto a treatment state or arrangement for delivering energy at thetreatment site and providing therapeutically-effectiveelectrically-induced and/or thermally-induced renal neuromodulation. Insome embodiments, the neuromodulation assembly 21 may be placed ortransformed into the deployed state or arrangement via remote actuation,e.g., via an actuator 36, such as a knob, pin, or lever carried by thehandle 34. In other embodiments, however, the neuromodulation assembly21 may be transformed between the delivery and deployed states usingother suitable mechanisms or techniques.

The proximal end of the neuromodulation assembly 21 can be carried by oraffixed to the distal portion 20 of the elongated shaft 16. A distal endof the neuromodulation assembly 21 may terminate with, for example, anatraumatic rounded tip or cap. Alternatively, the distal end of theneuromodulation assembly 21 may be configured to engage another elementof the system 10 or treatment device 12. For example, the distal end ofthe neuromodulation assembly 21 may define a passageway for engaging aguide wire (not shown) for delivery of the treatment device usingover-the-wire (“OTW”) or rapid exchange (“RX”) techniques. The treatmentdevice 12 can also be a steerable or non-steerable catheter device(e.g., a guide catheter) configured for use without a guide wire. Bodylumens (e.g., ducts or internal chambers) can be treated, for example,by non-percutaneously passing the shaft 16 and neuromodulation assembly21 through externally accessible passages of the body or other suitablemethods.

The console 26 can be configured to generate a selected form andmagnitude of energy for delivery to the target treatment site via theneuromodulation assembly 21. A control mechanism, such as a foot pedal32, may be connected (e.g., pneumatically connected or electricallyconnected) to the console 26 to allow an operator to initiate, terminateand, optionally, adjust various operational characteristics of theconsole 26, including, but not limited to, power delivery. The system 10may also include a remote control device (not shown) that can bepositioned in a sterile field and operably coupled to theneuromodulation assembly 21. The remote control device can be configuredto allow for selective activation of the neuromodulation assembly 21. Inother embodiments, the remote control device may be built into thehandle assembly 34. The console 26 can be configured to deliver thetreatment energy via an automated control algorithm 30 and/or under thecontrol of the clinician. In addition, the console 26 may include one ormore evaluation and/or feedback algorithms 31 to provide feedback to theclinician before, during, and/or after therapy.

The console 26 can further include a device or monitor that may includeprocessing circuitry, such as a microprocessor, and a display 33. Theprocessing circuitry may be configured to execute stored instructionsrelating to the control algorithm 30. The console 26 may be configuredto communicate with the treatment device 12 (e.g., via a cable 28) tocontrol the neuromodulation assembly and/or to send signals to orreceive signals from the nerve monitoring device. The display 33 may beconfigured to provide indications of power levels or sensor data, suchas audio, visual or other indications, or may be configured tocommunicate information to another device. For example, the console 26may also be configured to be operably coupled to a catheter lab screenor system for displaying treatment information, such as nerve activitybefore and/or after treatment.

In certain embodiments, a neuromodulation device for use in the methodsdisclosed herein may combine two or more energy modalities. For example,the device may include both a hyperthermic source of ablative energy anda hypothermic source, making it capable of, for example, performing bothRF neuromodulation and cryo-neuromodulation. The distal end of thetreatment device may be straight (for example, a focal catheter),expandable (for example, an expanding mesh or balloon), or have anyother configuration. For example, the distal end of the treatment devicecan be at least partially helical/spiral in the deployed state.Additionally or alternatively, the treatment device may be configured tocarry out one or more non-ablative neuromodulatory techniques. Forexample, the device may comprise a means for diffusing a drug orpharmaceutical compound at the target treatment area (e.g., a distalspray nozzle).

VI. SELECTED EXAMPLES OF TREATMENT PROCEDURES FOR RENAL NEUROMODULATION

A. Achieving Intravascular Access to the Renal Artery

In accordance with the present technology, neuromodulation of a leftand/or right renal plexus RP, which is intimately associated with a leftand/or right renal artery, may be achieved through intravascular access.As FIG. 5A shows, blood moved by contractions of the heart is conveyedfrom the left ventricle of the heart by the aorta. The aorta descendsthrough the thorax and branches into the left and right renal arteries.Below the renal arteries, the aorta bifurcates at the left and rightiliac arteries. The left and right iliac arteries descend, respectively,through the left and right legs and join the left and right femoralarteries.

As FIG. 5B shows, the blood collects in veins and returns to the heart,through the femoral veins into the iliac veins and into the inferiorvena cava. The inferior vena cava branches into the left and right renalveins. Above the renal veins, the inferior vena cava ascends to conveyblood into the right atrium of the heart. From the right atrium, theblood is pumped through the right ventricle into the lungs, where it isoxygenated. From the lungs, the oxygenated blood is conveyed into theleft atrium. From the left atrium, the oxygenated blood is conveyed bythe left ventricle back to the aorta.

As will be described in greater detail later, the femoral artery may beaccessed and cannulated at the base of the femoral triangle justinferior to the midpoint of the inguinal ligament. A catheter may beinserted percutaneously into the femoral artery through this accesssite, passed through the iliac artery and aorta, and placed into eitherthe left or right renal artery. This route comprises an intravascularpath that offers minimally invasive access to a respective renal arteryand/or other renal blood vessels.

The wrist, upper arm, and shoulder region provide other locations forintroduction of catheters into the arterial system. For example,catheterization of either the radial, brachial, or axillary artery maybe utilized in select cases. Catheters introduced via these accesspoints may be passed through the subclavian artery on the left side (orvia the subclavian and brachiocephalic arteries on the right side),through the aortic arch, down the descending aorta and into the renalarteries using standard angiographic technique.

B. Properties and Characteristics of the Renal Vasculature

Properties and characteristics of the renal vasculature imposechallenges to both access and treatment methods, and to system/devicedesigns. Since neuromodulation of a left and/or right renal plexus RPmay be achieved in accordance with embodiments of the present technologythrough intravascular access, various aspects of the design ofapparatus, systems, and methods for achieving such renal neuromodulationare disclosed herein. Aspects of the technology disclosed herein addressadditional challenges associated with variation of physiologicalconditions and architecture across the patient population and/or withina specific patient across time, as well as in response to diseasestates, such as hypertension, atherosclerosis, vascular disease, chronicinflammatory condition, insulin resistance, diabetes, metabolicsyndrome, etc. For example, the design of the intravascular device andtreatment protocols can address not only material/mechanical, spatial,fluid dynamic/hemodynamic and/or thermodynamic properties, but alsoprovide particular algorithms and feedback protocols for deliveringenergy and obtaining real-time confirmatory results of successfullydelivering energy to an intended target location in a patient-specificmanner.

As discussed previously, a catheter may be advanced percutaneously intoeither the left or right renal artery via a minimally invasiveintravascular path. However, minimally invasive renal arterial accessmay be challenging, for example, because as compared to some otherarteries that are routinely accessed using catheters, the renal arteriesare often extremely tortuous, may be of relatively small diameter,and/or may be of relatively short length. Furthermore, renal arterialatherosclerosis is common in many patients, particularly those withcardiovascular disease. Renal arterial anatomy also may varysignificantly from patient to patient, which further complicatesminimally invasive access. Significant inter-patient variation may beseen, for example, in relative tortuosity, diameter, length, and/oratherosclerotic plaque burden, as well as in the take-off angle at whicha renal artery branches from the aorta. Apparatus, systems and methodsfor achieving renal neuromodulation via intravascular access can accountfor these and other aspects of renal arterial anatomy and its variationacross the patient population when minimally invasively accessing arenal artery. For example, spiral or helical CT technology can be usedto produce 3D images of the vascular features for individual patients,and intravascular path choice as well as device size/diameter, length,flexibility, etc. can be selected based upon the patient's specificvascular features.

In addition to complicating renal arterial access, specifics of therenal anatomy also complicate establishment of stable contact betweenneuromodulatory apparatus and a luminal surface or wall of a renal bloodvessel. When the neuromodulatory apparatus includes an energy deliveryelement, such as an electrode, transducer, or a cryotherapeutic device,consistent positioning and appropriate contact force applied by theenergy or cryotherapy delivery element to the vessel wall, and adhesionbetween the applicator and the vessel wall can be important forpredictability. However, navigation can be impeded by the tight spacewithin a renal artery RA, as well as tortuosity of the artery.Furthermore, establishing consistent contact can be complicated bypatient movement, respiration, and/or the cardiac cycle because thesefactors may cause significant movement of the renal artery RA relativeto the aorta, and the cardiac cycle may transiently distend the renalartery RA (i.e., cause the wall of the artery to pulse). To addressthese challenges, the treatment device or applicator may be designedwith relative sizing and flexibility considerations. For example, therenal artery may have an internal diameter in a range of about 2-10 mmand the treatment device can be delivered using a 3, 4, 5, 6, 7 French,or in some cases, an 8 French sized catheter. To address challengesassociated with patient and/or arterial movement during treatment, thetreatment device and neuromodulation system can be configured to usesensory feedback, such as impedance and temperature, to detectinstability and to alert the operator to reposition the device and/or totemporarily stop treatment. In other embodiments, energy deliveryalgorithms can be varied in real-time to account for changes detecteddue to patient and/or arterial movement. In further examples, thetreatment device may include one or more modifications or movementresistant enhancements such as atraumatic friction knobs or barbs on anoutside surface of the device for resisting movement of the devicerelative to the desired tissue location, positionable balloons forinflating and holding the device in a consistent and stable positionduring treatment, or the device can include a cryogenic component thatcan temporarily freeze or adhere the device to the desired tissuelocation.

After accessing a renal artery and facilitating stable contact betweenneuromodulatory apparatus and a luminal surface of the artery, nerves inand around the adventitia of the artery can be modulated via theneuromodulatory apparatus. Effectively applying thermal treatment fromwithin a renal artery is non-trivial given the potential clinicalcomplications associated with such treatment. For example, the intimaand media of the renal artery are highly vulnerable to thermal injury.As discussed in greater detail below, the intima-media thicknessseparating the vessel lumen from its adventitia means that target renalnerves may be multiple millimeters distant (e.g., 1-3 mm) from theluminal surface of the artery. Sufficient energy can be delivered to orheat removed from the target renal nerves to modulate the target renalnerves without excessively cooling or heating the vessel wall to theextent that the wall is frozen, desiccated, or otherwise potentiallyaffected to an undesirable extent. For example, when employing energymodalities such as RF or ultrasound, energy delivery can be focused on alocation further from the interior vessel wall. In one embodiment, themajority of the RF or ultrasound energy can be focused on a location(e.g., a “hot spot”) 1-3 mm beyond the interior surface of the vesselwall. The energy will dissipate from the hot spot in a radiallydecreasing manner. Thus, the targeted nerves can be modulated withoutdamage to the luminal surface of the vessel. A potential clinicalcomplication associated with excessive heating is thrombus formationfrom coagulating blood flowing through the artery. Given that thisthrombus may cause a kidney infarct, thereby causing irreversible damageto the kidney, thermal treatment from within the renal artery RA can beapplied carefully. Accordingly, the complex fluid mechanics andthermodynamic conditions present in the renal artery during treatment,particularly those that may impact heat transfer dynamics at thetreatment site, may be important in applying energy (e.g., heatingthermal energy) and/or removing heat from the tissue (e.g., coolingthermal conditions) from within the renal artery. Accordingly, sensoryfeedback, such as impedance and temperature, can be used to assesswhether a desired energy distribution is administered at the treatmentsite and can, in some instances, be used to change an energy deliveryalgorithm in real-time to adjust for varying fluctuations in theproperties and conditions affecting heat transfer dynamics at thetreatment site.

The neuromodulatory apparatus can also be configured to allow foradjustable positioning and repositioning of an energy delivery elementor a cryotherapeutic device, within the renal artery since location oftreatment may also impact clinical efficacy. For example, it may betempting to apply a full circumferential treatment from within the renalartery given that the renal nerves may be spaced circumferentiallyaround a renal artery. In some situations, full-circle lesion likelyresulting from a continuous circumferential treatment may be potentiallyrelated to renal artery stenosis. Therefore, the formation of morecomplex lesions along a longitudinal dimension of the renal artery viathe cryotherapeutic devices or energy delivery elements and/orrepositioning of the neuromodulatory apparatus to multiple treatmentlocations may be desirable. It should be noted, however, that a benefitof creating a circumferential lesion or ablation may outweigh thepotential of renal artery stenosis or the risk may be mitigated withcertain embodiments or in certain patients and creating acircumferential lesion or ablation could be a goal. Additionally,variable positioning and repositioning of the neuromodulatory apparatusmay prove to be useful in circumstances where the renal artery isparticularly tortuous or where there are proximal branch vessels off therenal artery main vessel, making treatment in certain locationschallenging.

Blood flow through a renal artery may be temporarily occluded for ashort time with minimal or no complications. However, occlusion for asignificant amount of time can be avoided in some cases to preventinjury to the kidney such as ischemia. It can be beneficial to avoidocclusion altogether or, if occlusion is beneficial, to limit theduration of occlusion, for example to 2-5 minutes.

C. Neuromodulation of Renal Sympathetic Nerve at Treatment Site

FIG. 6 illustrates modulating renal nerves with an embodiment of thesystem 10 (FIG. 4). The treatment device 12 provides access to the renalplexus RP through an intravascular path P, such as a percutaneous accesssite in the femoral (illustrated), brachial, radial, or axillary arteryto a targeted treatment site within a respective renal artery RA. Asillustrated, a section of the proximal portion 18 of the shaft 16 isexposed externally of the patient. By manipulating the proximal portion18 of the shaft 16 from outside the intravascular path P, the clinicianmay advance the shaft 16 through the sometimes tortuous intravascularpath P and remotely manipulate the distal portion 20 of the shaft 16.Image guidance, e.g., CT, fluoroscopy, intravascular ultrasound (IVUS),optical coherence tomography (OCT), or another suitable guidancemodality, or combinations thereof, may be used to aid the clinician'smanipulation. Further, in some embodiments, image guidance components(e.g., IVUS, OCT) may be incorporated into the treatment device 12. Insome embodiments, the shaft 16 and the neuromodulation assembly 21 canbe 3, 4, 5, 6, or 7 French or another suitable size. Furthermore, theshaft 16 and the neuromodulation assembly 21 can be partially or fullyradiopaque and/or can include radiopaque markers corresponding tomeasurements, e.g., every 5 cm.

After the neuromodulation assembly 21 is adequately positioned in therenal artery RA, it can be radially expanded or otherwise deployed usingthe handle 34 or other suitable control mechanism until theneuromodulation assembly is positioned at its target site and in stablecontact with the inner wall of the renal artery RA. The purposefulapplication of energy from the neuromodulation assembly can then beapplied to tissue to induce one or more desired neuromodulating effectson localized regions of the renal artery RA and adjacent regions of therenal plexus RP, which lay intimately within, adjacent to, or in closeproximity to the adventitia of the renal artery RA. The neuromodulatingeffects may include denervation, thermal ablation, and non-ablativethermal alteration or damage (e.g., via sustained heating and/orresistive heating). The purposeful application of the energy may achieveneuromodulation along all or at least a portion of the renal plexus RP.

In the deployed state, the neuromodulation assembly 21 can be configuredto contact an inner wall of a vessel of the renal vasculature and toform a suitable lesion or pattern of lesions without the need forrepositioning. For example, the neuromodulation assembly 21 can beconfigured to form a single lesion or a series of lesions, e.g.,overlapping and/or non-overlapping. In some embodiments, the lesion(s)(e.g., pattern of lesions) can extend around generally the entirecircumference of the vessel, but can still be non-circumferential atlongitudinal segments or zones along a lengthwise portion of the vessel.This can facilitate precise and efficient treatment with a lowpossibility of vessel stenosis. In other embodiments, theneuromodulation assembly 21 can be configured form apartially-circumferential lesion or a fully-circumferential lesion at asingle longitudinal segment or zone of the vessel. During treatment, theneuromodulation assembly 21 can be configured for partial or fullocclusion of a vessel. Partial occlusion can be useful, for example, toreduce ischemia, while full occlusion can be useful, for example, toreduce interference (e.g., warming or cooling) caused by blood flowthrough the treatment location. In some embodiments, the neuromodulationassembly 21 can be configured to cause therapeutically-effectiveneuromodulation (e.g., using ultrasound energy) without contacting avessel wall.

As mentioned previously, the methods disclosed herein may use a varietyof suitable energy modalities, including RF energy, pulsed RF energy,microwave energy, laser, optical energy, ultrasound energy (e.g.,intravascularly delivered ultrasound, extracorporeal ultrasound, HIFU),magnetic energy, direct heat, cryotherapy, radiation (e.g., infrared,visible, gamma), or a combination thereof. Alternatively or in additionto these techniques, the methods may utilize one or more non-ablativeneuromodulatory techniques. For example, the methods may utilizenon-ablative SNS neuromodulation by removal of target nerves (e.g.,surgically), injection of target nerves with a destructive drug orpharmaceutical compound, or treatment of the target nerves withnon-ablative energy modalities (e.g., laser or light energy). In certainembodiments, the amount of reduction of the sympathetic nerve activitymay vary depending on the specific technique being used.

In certain embodiments, a neuromodulation device for use in the methodsdisclosed herein may combine two or more energy modalities. For example,the device may include both a hyperthermic source of ablative energy anda hypothermic source, making it capable of, for example, performing bothRF neuromodulation and cryo-neuromodulation. The distal end of thetreatment device may be straight (for example, a focal catheter),expandable (for example, an expanding mesh or cryoballoon), or have anyother configuration. For example, the distal end of the treatment devicecan be at least partially helical/spiral in the deployed state.Additionally or alternatively, the treatment device may be configured tocarry out one or more non-ablative neuromodulatory techniques. Forexample, the device may comprise a means for diffusing a drug orpharmaceutical compound at the target treatment area (e.g., a distalspray nozzle).

Furthermore, a treatment procedure can include treatment at any suitablenumber of treatment locations, e.g., a single treatment location, twotreatment locations, or more than two treatment locations. In someembodiments, different treatment locations can correspond to differentportions of the renal artery RA, the renal vein, and/or other suitablestructures proximate tissue having relatively high concentrations ofrenal nerves. The shaft 16 can be steerable (e.g., via one or more pullwires, a steerable guide or sheath catheter, etc.) and can be configuredto move the neuromodulation assembly 21 between treatment locations. Ateach treatment location, the neuromodulation assembly 21 can beactivated to cause modulation of nerves proximate the treatmentlocation. Activating the neuromodulation assembly 21 can include, forexample, heating, cooling, stimulating, or applying another suitabletreatment modality at the treatment location. Activating theneuromodulation assembly 21 can further include applying various energymodalities at varying power levels, intensities and for variousdurations for achieving modulation of nerves proximate the treatmentlocation. In some embodiments, power levels, intensities and/ortreatment duration can be determined and employed using variousalgorithms for ensuring modulation of nerves at select distances (e.g.,depths) away from the treatment location. Furthermore, as notedpreviously, in some embodiments, the neuromodulation assembly 21 can beconfigured to introduce (e.g., inject) a chemical (e.g., a drug or otheragent) into target tissue at the treatment location. Such chemicals oragents can be applied at various concentrations depending on treatmentlocation and the relative depth of the target nerves.

As discussed, the neuromodulation assembly 21 can be positioned at atreatment location within the renal artery RA, for example, via acatheterization path including a femoral artery and the aorta, oranother suitable catheterization path, e.g., a radial or brachialcatheterization path. Catheterization can be guided, for example, usingimaging, e.g., magnetic resonance, computed tomography, fluoroscopy,ultrasound, intravascular ultrasound, optical coherence tomography, oranother suitable imaging modality. The neuromodulation assembly 21 canbe configured to accommodate the anatomy of the renal artery RA, therenal vein, and/or another suitable structure. For example, theneuromodulation assembly 21 can include a balloon (not shown) configuredto inflate to a size generally corresponding to the internal size of therenal artery RA, the renal vein, and/or another suitable structure. Insome embodiments, the neuromodulation assembly 21 can be an implantabledevice and a treatment procedure can include locating theneuromodulation assembly 21 at the treatment location using the shaft 16fixing the neuromodulation assembly 21 at the treatment location,separating the neuromodulation assembly 21 from the shaft 16, andwithdrawing the shaft 16. Other treatment procedures for modulation ofrenal nerves in accordance with embodiments of the present technologyare also possible.

FIG. 7 is a block diagram illustrating a method 700 of modulating renalnerves using the system 10 described above with reference to FIGS. 4 and6. With reference to FIGS. 4, 6 and 7 together, the method 700 canoptionally include selecting a suitable candidate patient having anidentifiable depression risk factor for performing renal neuromodulation(block 702). For example, a suitable patient can include a patienthaving a depression risk score corresponding to a depression status inthe patient that is above a threshold level, a patient having one ormore measurable risk factors for developing depression, a patient havingone or more identifiable depression symptoms during or following anadverse life event or circumstance, a patient diagnosed with depression,an at-risk patient having a history of depression and/or a geneticpredisposition for developing depression, and/or a patient with historyof cardiovascular disease or stroke and having one or more identifiablerisk factors for developing depression.

Modulating SNS nerves innervating the kidneys is expected to lower renalnerve activity and/or central SNS nerve activity, thereby inhibiting,preventing, slowing, disrupting or reversing physiological pathwaysassociated with depression and/or lowering a risk associated withdeveloping depression in the patient either before or after on-set ofone or more depression-related symptoms. In particular, targeting therenal nerve for neuromodulation is anticipated to reduce renalnorepinephrine spillover, whole body norepinephrine spillover, andreduce central sympathetic drive (e.g., reduce a level of efferent SNSnerve firing) in the patient, thereby inhibiting, preventing, slowing,disrupting or reversing depression and/or symptoms associated withdepression and/or conditions proposed to increase a patient's risk ofdeveloping depression. Without being bound by theory, renalneuromodulation is anticipated to address the hyperactivity of the SNSand/or the elevated SNS tone present in patients with depression and/orpatients having one or more risk factors of developing depression. Inother instances, and without being bound by theory, an overactive orhyperactive SNS is believed to be an underlying contributing cause ofdepression and renal neuromodulation is anticipated to prevent orprohibit the development of a hyperactive or overactive SNS in a patientprior to or subsequent to experiencing an adverse life event orcircumstance that precipitates, for example, excessive or chronicpsychological stress.

The method 700 can include intravascularly locating the neuromodulationassembly 21 in a delivery state (e.g., low-profile configuration) to afirst target site in or near a first renal blood vessel (e.g., firstrenal artery) or first renal ostium (block 705). The treatment device 12and/or portions thereof (e.g., the neuromodulation assembly 21) can beinserted into a guide catheter or sheath to facilitate intravasculardelivery of the neuromodulation assembly 21. In certain embodiments, forexample, the treatment device 12 can be configured to fit within an 8 Frguide catheter or smaller (e.g., 7 Fr, 6 Fr, etc.) to access smallperipheral vessels. A guide wire (not shown) can be used to manipulateand enhance control of the shaft 16 and the neuromodulation assembly 21(e.g., in an OTW or a RX configuration). In some embodiments, radiopaquemarkers and/or markings on the treatment device 12 and/or the guide wirecan facilitate placement of the neuromodulation assembly 21 at the firsttarget site (e.g., a first renal artery or first renal ostium of thepatient). In some embodiments, a contrast material can be delivereddistally beyond the neuromodulation assembly 21, and fluoroscopy and/orother suitable imaging techniques can be used to aid in placement of theneuromodulation assembly 21 at the first target site.

The method 700 can further include connecting the treatment device 12 tothe console 26 (block 710), and determining whether the neuromodulationassembly 21 is in the correct position at the target site and/or whetherthe neuromodulation assembly (e.g., electrodes or cryotherapy balloon)is functioning properly (block 715). Once the neuromodulation assembly21 is properly located at the first target site and no malfunctions aredetected, the console 26 can be manipulated to initiate application ofan energy field to the target site to cause electrically-induced and/orthermally-induced partial or full denervation of the kidney (e.g., usingelectrodes or cryotherapeutic devices). Accordingly, heating and/orcooling of the neuromodulation assembly 21 causes modulation of renalnerves at the first target site to cause partial or full denervation ofthe kidney associated with the first target site (block 720).

In one example, the treatment device 12 can be an RF energy emittingdevice and RF energy can be delivered through energy delivery elementsor electrodes to one or more locations along the inner wall of the firstrenal blood vessel or first renal ostium for predetermined periods oftime (e.g., 120 seconds). In some embodiments, multiple treatments(e.g., 4-6) may be administered in both the left and right renal bloodvessels (e.g., renal arteries) to achieve a desired coverage and/ordesired inhibition of sympathetic neural activity in the body.

In some embodiments, a treatment procedure can include applying asuitable treatment modality at a treatment location in a testing step(not shown) followed by a treatment step. The testing step, for example,can include applying the treatment modality at a lower intensity and/orfor a shorter duration than during the treatment step. This can allow anoperator to determine (e.g., by neural activity sensors and/or patientfeedback) whether nerves proximate the treatment location are suitablefor modulation. Performing a testing step can be particularly useful fortreatment procedures in which targeted nerves are closely associatedwith nerves that could cause undesirable side effects if modulatedduring a subsequent treatment step.

A technical objective of a treatment may be, for example, to heat tissueto a desired depth (e.g., at least about 3 mm) to a temperature thatwould lesion a nerve (e.g., about 65° C.). A clinical objective of theprocedure typically is to treat (e.g., lesion) a sufficient number ofrenal nerves (either efferent or afferent nerves) to cause a reductionin sympathetic tone or drive to the kidneys. If the technical objectiveof a treatment is met (e.g., tissue is heated to about 65° C. to a depthof about 3 mm) the probability of forming a lesion of renal nerve tissueis high. The greater the number of technically successful treatments,the greater the probability of modulating a sufficient proportion ofrenal nerves, and thus the greater the probability of clinical success.

In a specific example of using RF energy for renal nerve modulation, aclinician can commence treatment which causes the control algorithm 30(FIG. 4) to initiate instructions to the generator (not shown) togradually adjust its power output to a first power level (e.g., 5 watts)over a first time period (e.g., 15 seconds). The power increase duringthe first time period is generally linear. As a result, the generatorincreases its power output at a generally constant rate of power/time.Alternatively, the power increase may be non-linear (e.g., exponentialor parabolic) with a variable rate of increase. Once the first powerlevel and the first time are achieved, the algorithm may hold at thefirst power level until a second predetermined period of time haselapsed (e.g., 3 seconds). At the conclusion of the second period oftime, power is again increased by a predetermined increment (e.g., 1watt) to a second power level over a third predetermined period of time(e.g., 1 second). This power ramp in predetermined increments of about 1watt over predetermined periods of time may continue until a maximumpower P_(MAX) is achieved or some other condition is satisfied. In oneembodiment, P_(MAX) is 8 watts. In another embodiment P_(MAX) is 10watts. Optionally, the power may be maintained at the maximum powerP_(MAX) for a desired period of time or up to the desired totaltreatment time (e.g., up to about 120 seconds).

In another specific example, the treatment device 12 can be a cryogenicdevice and cryogenic cooling can be applied for one or more cycles(e.g., for 30 second increments, 60 second increments, 90 secondincrements, etc.) in one or more locations along the circumferenceand/or length of the first renal artery or first renal ostium. Thecooling cycles can be, for example, fixed periods or can be fully orpartially dependent on detected temperatures (e.g., temperaturesdetected by a thermocouple (not shown) of the neuromodulation assembly21). In some embodiments, a first stage can include cooling tissue untila first target temperature is reached. A second stage can includemaintaining cooling for a set period, such as 15-180 seconds (e.g., 90seconds). A third stage can include terminating or decreasing cooling toallow the tissue to warm to a second target temperature higher than thefirst target temperature. A fourth stage can include continuing to allowthe tissue to warm for a set period, such as 10-120 seconds (e.g., 60seconds). A fifth stage can include cooling the tissue until the firsttarget temperature (or a different target temperature) is reached. Asixth stage can include maintaining cooling for a set period, such as15-180 seconds (e.g., 90 seconds). A seventh stage can, for example,include allowing the tissue to warm completely (e.g., to reach a bodytemperature).

The neuromodulation assembly 21 can then be located at a second targetsite in or near a second renal blood vessel (e.g., second renal artery)or second renal ostium (block 725), and correct positioning of theassembly 21 can be determined (block 730). In selected embodiments, acontrast material can be delivered distally beyond the neuromodulationassembly 21 and fluoroscopy and/or other suitable imaging techniques canbe used to locate the second renal artery. The method 700 continues byapplying targeted heat or cold to effectuate renal neuromodulation atthe second target site to cause partial or full denervation of thekidney associated with the second target site (block 735).

After providing the therapeutically-effective neuromodulation energy(e.g., cryogenic cooling, RF energy, ultrasound energy, etc.), themethod 700 may also include removing the treatment device 12 (e.g.,catheter) and the neuromodulation assembly 21 from the patient (block740). In some embodiments, the neuromodulation assembly 21 can be animplantable device (not shown) and a treatment procedure can includeimplanting the neuromodulation assembly 21 at a suitable treatmentlocation within the patient. Other treatment procedures for modulationof target sympathetic nerves in accordance with embodiments of thepresent technology are also possible.

The method 700 may also include determining whether the neuromodulationsufficiently modulated nerves or other neural structures proximate thefirst and second target sites (block 745). For example, the process ofdetermining whether the neuromodulation therapeutically treated thenerves can include determining whether nerves were sufficientlymodulated or otherwise disrupted to reduce, suppress, inhibit, block orotherwise affect the afferent and/or efferent renal signals (e.g., byevaluation of suitable biomarkers, stimulation and recording of nervesignals, etc.). Examples of suitable biomarkers and their detection aredescribed in International Patent Application No. PCT/US2013/030041,filed Mar. 8, 2013, and International Patent Application No.PCT/US2015/047568, filed Aug. 28, 2015, the disclosures of which areincorporated herein by reference in their entireties. Other suitabledevices and technologies, such as endovascular intraoperative renalnerve monitoring devices are described in International PatentApplication No. PCT/US12/63759, filed Jan. 29, 2013, and incorporatedherein by reference in its entirety.

In a further embodiment, patient assessment could include determiningwhether the neuromodulation therapeutically treated the patient for oneor more symptoms associated with depression, e.g., core depressionsymptoms (e.g., feelings of sadness, apathy, mood swings, anhedonia,guilt, anxiety, excess sleepiness, fatigue, excessive hunger, loss ofappetite, irritability, excessive crying, lack of concentration,slowness in activity and thoughts of suicide in the patient, etc.),sleep disturbances (e.g., insomnia, restless sleep), systemicinflammation, and undesirable elevations in heart rate, blood pressure,and skin conductance, among others. Assessment of certain suitablebiomarkers and/or nerve signals may be made immediately or shortly afterneuromodulation (e.g., about 15 minutes, about 24 hours, or about 7 dayspost-neuromodulation). In further embodiments, patient assessment couldbe performed at time intervals (e.g., about 1 month, 3 months, 6 months,12 months) following neuromodulation treatment. For example, the patientcan be assessed for measurements of blood pressure, blood pressurevariability, nocturnal blood pressure “dipping”, MSBP level, skinconductance, resting heart rate, sleep patterns or quality, measures ofsympathetic activity (e.g., MSNA, renal and/or total body norepinephrinespillover, plasma norepinephrine levels, and heart rate variability),peripheral inflammatory markers (e.g., IL-6, CRP, etc.), NPY level,measures of HPA axis function (e.g., glucocorticoid levels (e.g., inhair, urine, plasma, etc.), glucocorticoid resistance, CAR level, CRHlevel, etc.), sodium level, potassium level, plasma aldosteroneconcentration, plasma renin activity, aldosterone-to-renin ratio, saltsuppression, levels of components of the RAAS (e.g., angiotensinogen IIlevels), urinary Na⁺/K⁺ levels, markers of renal damage or measures ofrenal function (e.g. creatinine level, estimated glomerular filtrationrate, blood urea nitrogen level, creatinine clearance, cystatin-C level,NGAL levels, KIM-1 levels, presence of proteinuria or microalbuminuria,urinary albumin creatinine ratio), and/or a post-neuromodulationdepression risk score (e.g., via a depression screening tool fordetermining a severity of depression).

In other embodiments, various steps in the method 700 can be modified,omitted, and/or additional steps may be added. In further embodiments,the method 700 can have a delay between applyingtherapeutically-effective neuromodulation energy to a first target siteat or near a first renal artery or first renal ostium and applyingtherapeutically-effective neuromodulation energy to a second target siteat or near a second renal artery or second renal ostium. For example,neuromodulation of the first renal artery can take place at a firsttreatment session, and neuromodulation of the second renal artery cantake place a second treatment session at a later time.

FIG. 8 is a block diagram illustrating a method 800 for improving adepression risk score for a patient in accordance with aspects of thepresent technology. In a first step, the method 800 can includedetermining an initial depression risk score for a patient (block 802).For example, one or more suitable depression risk score calculatingtechniques or tools can be used to establish a depression risk scorecorresponding to a depression status in the patient as described above(Bech, P., et al., BMC Psychiatry, 2015, 15:190). At decision block 804,the initial depression risk score can be evaluated against a thresholdrisk score or value. If the initial depression risk score is not abovethe threshold risk score, there is no need to reduce the depression riskscore for the patient at the current time and no treatment is selectedto perform (block 806). In such a patient, a clinician may recommendmonitoring the patient's depression risk score over time. For example, aclinician can optionally determine an updated initial depression riskscore for the patient after a determined time lapse (e.g., 1 month, 2months, 3 months, 6 months, 12 months, etc.) (block 808). Following eachdepression risk score evaluation (block 808), the patient's depressionrisk score is evaluated against the threshold risk score or value(decision block 804).

If the patient's depression risk score from method step 802, or from theoptional method step 808, is higher than the threshold risk score, themethod 800 can include performing a neuromodulation procedure in thepatient (block 810). In one example, the patient can be a suitablecandidate patient as identified in method step 702 of method 700described above, and the neuromodulation procedure can be performed asdescribed in continuing steps of method 700. In other embodiments, aclinician can perform an alternative neuromodulation procedure at methodstep 810. For example, neuromodulation of other target (e.g., non-renal)sympathetic nerves or neuromodulation in a single renal blood vessel(e.g., renal artery) may be performed on the patient.

The method 800 is expected to improve the patient's depression riskscore or reduce a probability of the patient developing depression.Optionally, the clinician can further determine a post-neuromodulationdepression risk score for the patient (block 812). For example, thepatient can be evaluated using the depression risk score tool to assessthe patient's post-neuromodulation depression status or, alternatively,risk of developing depression. If the post-neuromodulation depressionrisk score is determined for the patient in step 812, the methodincludes comparing the post-neuromodulation depression risk score to theinitial depression risk score (block 814). In determining if the method800 is successful, the post-neuromodulation depression risk score islower than the patient's initial depression risk score as determined instep 802 (or updated initial depression risk score as determined in step808). In some examples, the post-neuromodulation depression risk scoreis lower than the initial depression risk score by about 5%, about 10%,about 20% or about 30%. In other embodiments, the post-neuromodulationdepression risk score is lower than the initial depression risk score bymore than 30%. In certain embodiments, the post-neuromodulationdepression risk score can be lower than the threshold risk score.

VII. EXPERIMENTAL EXAMPLES Example 1

This section describes an example of the outcome of renalneuromodulation on human patients. A total of 45 patients (mean age of58±9 years) diagnosed with essential hypertension were treated withpercutaneous, catheter based renal nerve ablation. Treatment included RFenergy delivery to the renal artery using a single-electrode SymplicityFlex™ catheter commercially available from Medtronic, Inc., of 710Medtronic Parkway, Minneapolis, Minn. 55432-5604. In this human trial, aradiotracer dilution method was used to assess overflow ofnorepinephrine from the kidneys into circulation before and 15-30 daysafter the procedure in 10 patients. Bilateral renal-nerve ablationresulted in a marked reduction in mean norepinephrine spillover fromboth kidneys: 47% (95% confidence interval) one month after treatment.

In a similar human trial where bilateral renal nerve ablation wasperformed in 70 patients, whole-body norepinephrine levels (i.e., ameasure of “total” sympathetic activity), fell by nearly 50% after renalnerve ablation and measurement of muscle sympathetic nerve activityshowed a drop of 66% over 6 months, further supporting the conclusionthat total sympathetic dive was reduced by the renal denervationprocedure in this patient group.

Example 2

Example 2 describes the outcome of catheter-based renal neuromodulationon human patients diagnosed with hypertension. Patients selected havinga baseline systolic blood pressure of 160 mm Hg or more (≥150 mm Hg forpatients with type 2 diabetes) and taking three or more antihypertensivedrugs, were randomly allocated into two groups: 51 assessed in a controlgroup (antihypertensive drugs only) and 49 assessed in a treated group(undergone renal neuromodulation and antihypertensive drugs).

Patients in both groups were assessed at 6 months. Office-based bloodpressure measurements in the treated group were reduced by 32/12 mm Hg(SD 23/11, baseline of 178/96 mm Hg, p<0.0001), whereas they did notdiffer from baseline in the control group (change of I/O mm Hg, baselineof 178/97 mm Hg, p=0.77 systolic and p=0.83 diastolic). Between-groupdifferences in blood pressure at 6 months were 33/11 mm Hg (p<0.0001).At 6 months, 41 (84%) of 49 patients who underwent renal neuromodulationhad a reduction in systolic blood pressure of 10 mm Hg or more, comparedwith 18 (35%) of 51 control patients (p<0.0001).

Example 3

Example 3 describes the outcome of catheter-based renal neuromodulationon animal subjects in an additional experiment. In this example (andreferring to FIGS. 9A and 9B), studies using the pig model wereperformed using a multi-electrode Symplicity Spyral™ catheter or asingle-electrode Symplicity Flex™ catheter along with a Symplicity G3™generator. The catheters and generator are commercially available fromMedtronic, Inc. The catheters were used in these cohorts of animals(n=66) to create multiple RF ablations in the renal vasculature.Cortical axon density in the renal cortex (FIG. 9A) and renal corticalnorepinephrine (NE) concentration (FIG. 9B) were used as markers tomeasure procedural efficacy.

As shown in FIG. 9A, cortical axon area (per mm²) dropped approximatelygreater than 54% between a control group (n=64) and treated groups ofpigs (n=66) undergoing treatment. For pigs undergoing treatment with theSymplicity Flex™ catheter (n=54), an average of 4.1 lesions were formedin each animal. These pigs demonstrated a 56.9% increase innon-functional axonal area along the renal artery, and a 68% decrease incortical axon area as compared with the control group. For pigsundergoing treatment with the Symplicity Spyral™ catheter (n=12), anaverage of 4.0 lesions were formed in each animal. The pigs undergoingtreatment with the Symplicity Spyral™ catheter demonstrated a 47.3%increase in non-functional area along the renal artery, and a 54%decrease in cortical axon area relative to the control group. Withoutbeing bound by theory, it is believed that the loss of cortical axons isa likely consequence of nerve atrophy distal to the ablation sites.

FIG. 9B includes (a) a graph of normalized cortical axon area vs. renalNE concentration, and (b) a graph of renal NE concentration vs. extent(%) of nerve ablation. Referring to the table of FIG. 9A and the twographs of FIG. 9B together, cortical axon area correlates directly withrenal NE. In particular, pigs undergoing treatment with the SymplicityFlex™ catheter exhibited a 65% decrease in mean NE level compared withthe pigs in the control group. The pigs treated with the SymplicitySpyral™ catheter exhibited a 68% decrease in mean NE level compared withthe pigs in the control group. This is further shown by the first graphof FIG. 9B, which demonstrates that a decrease in cortical axon areacorrelates with a decrease in NE levels. Referring to the second graphof FIG. 9B, renal NE decrease is non-linear with increased loss of nerveviability along the artery (further extent (%) of nerve ablation). Thesefindings suggest that catheter-based renal neuromodulation exhibits arelatively consistent impact on sympathetic nerve function andviability, and further suggest that neuromodulation of SNS fibersinnervating a target tissue and/or organ (such as the kidney) result ina significant decrease in local NE concentration.

Example 4

Example 4 describes an example of the outcome of renal neuromodulationon human patients. Markers of cardiovascular inflammation and remodelingwere assessed (Dörr, O., et al., Clin Res Cardiol, 2015, 104: 175-184).A total of 60 patients (mean age of 67.9±9.6 years) diagnosed withresistant arterial hypertension were treated with percutaneous,catheter-based renal sympathetic denervation. Treatment included RFenergy delivery to the renal artery using a Symplicity® catheter systemcommercially available from Medtronic, Inc. In this human trial, atherapeutic response was defined as a systolic blood pressure (BP)reduction of >10 mmHg in the office blood pressure measurement 6 monthsafter renal denervation. Of the 60 patients, 49 patients (82%) wereclassified as responders with a mean systolic BP reduction of >10 mmHg.Venous blood samples for determination of biomarkers of inflammation(e.g., IL-6, high-sensitive C-reactive protein (hsCRP)) and markers ofvascular remodeling (matrix metalloproteinases (MMP-2 and MMP-9), tissueinhibitors of matrix metalloproteinases (TIMP-1)) were collected atbaseline (prior to renal denervation) and 6 months after renaldenervation for all patients.

Collected data from all patients demonstrated that bilateral renal nervedenervation resulted in a significant reduction in mean office systolicBP of 26.4 mmHg (169.3±11.3 mmHg at baseline vs. 142.9±13.8 mmHg atfollow-up; p<0.001). The procedure further resulted in a significantreduction in the serum levels of hsCRP (3.6 mg/dL at baseline vs. 1.7mg/dL at follow-up, p<0.001), and a significant reduction in thepro-inflammatory cytokine IL-6 (4.04 pg/mL at baseline vs. 2.2 pg/mL atfollow-up, p<0.001) six months after treatment. Additionally, theprocedure resulted in a significant increase in the serum levels ofMMP-9 (425.2 ng/mL at base line vs. 574.1 ng/mL at follow-up, p=0.02),and in serum levels of MMP-2 (192.3 ng/mL at baseline vs. 231.3 ng/mL atfollow-up, p<0.001). There were no significant changes in TIMP-1 6months after renal denervation. Notably, of non-responders (e.g.,patients with a BP reduction of <10 mmHg), serum levels of hsCRP stilldecreased (3.2 mg/dL at baseline vs. 2.4 mg/dL at follow-up, p=0.09),and serum levels of IL-6 still decreased (3.1 pg/mL at baseline vs. 2.7pg/mL at follow-up, p=0.16), although there was a significantly greaterbeneficial effect of renal denervation on biomarker levels in BPresponders when compared with non-responders.

These findings suggest that catheter-based renal neuromodulationexhibits a positive vascular and systemic effect on mediators ofinflammation, IL-6 and hsCRP, and inhibitors (MMP-9 and MMP-2) ofdeleterious cardiovascular remodeling. Low serum levels of MMP-9 andMMP-2 have been found to be essential to damaging vascular remodelingfound in essential hypertension and progression of end-organ damageThese findings suggest that levels of MMP-9 and MMP-2, which areinvolved in ECM turnover in different tissues, including the arterialwall, can be elevated post-renal neuromodulation, and, without beingbound by theory, are postulated to be beneficial in reversal of damageto the vessels caused by inflammation, cardiovascular disease and/orhypertension. As elevated inflammatory biomarkers, such as IL-6 and CRP,have been proposed as predictors and possible contributors of depressionetiology and/or incidence of depression, these results demonstrate thatrenal neuromodulation may be useful to reduce a severity of depression,reverse a depression diagnosis, or reduce a risk associated with thedevelopment of depression in susceptible or at risk patients (Halaris,A., Curr Topics Behav Neurosci, 2017, 31:45-70; Raison, C. L. andMiller, A. H., Cerebrum, 2013; Miller, A. H., et al., Biol Psychiatry,2009, 65: 732-741). In addition to lowering systolic BP in (responsive)hypertensive patients, these findings suggest that renal denervation hasa positive effect on biomarkers of inflammation (e.g., IL-6, hsCRP) andcardiovascular remodeling (e.g., MMP-2, MMP-9) separate from and inaddition to the effect on blood pressure.

Example 5

Example 5 describes an example of the effects of renal neuromodulationon nocturnal blood pressure using ambulatory 24-hour blood pressure (BP)monitoring in human patients. Elevated blood pressure during thenighttime as well as early morning hours (e.g., elevated morning surgein BP; “MSBP”) is associated with an increased risk of cardiovascularevents and strokes, and MSBP is associated with depression independentfrom “non-dipping” nocturnal blood pressure, with higher morning surgesassociated with higher levels of depressive symptoms, including pooreroverall sleep quality (FitzGerald, L., et al., J Hum Hypertens, 2012,26: 228-235; Kario, K., et al., Hypertension, 2015, 66:1130-1137). Inthis example, a total of 576 patients diagnosed with resistant arterialhypertension (e.g., baseline office systolic BP≥160 mm Hg and 24-hourambulatory systolic BP≥135 mm Hg) were either treated (“RDN treated”;n=382) with bilateral percutaneous, catheter-based renal sympatheticdenervation (mean age of 58±11 years) or blindly treated (“blindcontrol”; n=159) with a sham procedure (e.g., renal angiogram) or nottreated (“control”; n=19) (Kario, K., et al., Hypertension, 2015,66:1130-1137). Treatment included RF energy delivery to the renal arteryusing a Symplicity™ catheter system (Medtronic, Inc.). The renalneuromodulation (“RDN”) treated group received up to six ablationsrotated in 45 degree increments and approximately 5 mm apart for 2minutes each in both renal arteries. Treatments were delivered from thefirst distal main renal artery bifurcation to the ostium proximally andwere spaced longitudinally and rotationally under fluoroscopic guidance.BP variability, morning ambulatory, nighttime ambulatory and daytimeambulatory systolic BP was measured by 24-hour ambulatory BP monitoringbefore renal denervation and at 6 months after renal denervation.

In patients with resistant hypertension, renal denervation resulted insignificant reduction in ambulatory nighttime and morning BP. Forexample, mean ambulatory nighttime BP measurements in the RDN treatedgroup were reduced by 6.3±18.2 mm Hg (p<0.001; baseline of 151.5±18.3 mmHg, p=0.24), whereas they were not significantly reduced (−1.7±19.2 mmHg; p=0.233) from baseline (149.5±20.1 mm Hg, p=0.24) in the blindcontrol+control group 6 months post-neuromodulation. Further, meanambulatory morning BP measurements in the RDN treated group were reducedby 7.3±19.6 mm Hg (p<0.001; baseline of 161.2±17.2 mm Hg, p=0.24),whereas they were not significantly reduced (−3.2±21.0 mm Hg; p=0.046)from baseline (160.3±19.2 mm Hg, p=0.579) in the blind control+controlgroup 6 months post-neuromodulation. These findings suggest thatpatients with depression and treated with renal neuromodulation willhave decreased ambulatory nighttime systolic BP and decreased MSBP whichwill reduce the patient's likelihood (e.g., lower level of risk) ofdeveloping, progressing or worsening cardiovascular disease. Thesefindings further suggest that patients with depression and treated withrenal neuromodulation will improve one or more symptoms relating todepression and/or sleep disturbances (FitzGerald, L., et al., J HumHypertens, 2012, 26: 228-235).

Example 6

Example 6 describes a method for treating human patients diagnosed withdepression with renal neuromodulation and anticipated outcomes of suchtreatment. In this example, human patients diagnosed with depressionwill be treated with renal denervation and a method of treatmentincludes modulating nerve tissue surrounding the main renal artery(e.g., locations along the main renal vessel, locations at or near thebifurcation, etc.) and/or modulating nerve tissue surrounding one ormore primary branch trunks (e.g., proximal portion of one or moreprimary branch vessels distal to the bifurcation).

For patients undergoing distal main renal artery treatment, modulatingnerve tissue includes forming a plurality of spaced-apart lesions at thedistal segment of the renal artery and within a distance ofapproximately 6 mm proximal to the branch point within the renal arteryusing the Symplicity Spyral™ catheter, commercially available fromMedtronic, Inc. For example, a first (e.g., most distal) lesion can beformed about 5-6 mm proximal from the bifurcation. Othermulti-electrode, spiral/helical-shaped catheters for forming multiplelesions along the length of the vessel are also contemplated for thesemethods. For patients undergoing main artery treatment at a centralsegment of the main renal artery, the Symplicity Spyral™ catheter can beused to form a plurality of spaced-apart lesions (e.g., about 2 lesionsto about 4 lesions) in a spiral/helical pattern along the centralsegment of the main renal artery. The catheter may also be movedproximally and/or distally to form multiple sets of lesions during aprocedure.

For patients undergoing renal branch treatment, modulating nerve tissueincludes forming up to about four lesions (e.g., about 2 lesions toabout 4 lesions) in one or more primary branch trunks (e.g., from about1 mm to about 6 mm distal to the primary bifurcation, in regions greaterthan 2 mm distal to the primary bifurcation). Modulation of nerve tissueat branch trunk treatment sites and/or different combinations oftreatment sites within the renal vasculature (e.g., locations along themain renal vessel, locations at or near the bifurcation, etc.) can alsobe performed using the multi-electrode Symplicity Spyral™ catheter.Other multi-electrode, spiral/helical-shaped catheters having a tighterspiral/helix (e.g., smaller pitch) for forming multiple lesions close inproximity along the length of the vessel are contemplated for thesemethods.

In a particular example, a method for efficaciously neuromodulatingrenal nerve tissue in a human patient can include advancing amulti-electrode Symplicity Spyral™ catheter to a first renal arterybranch vessel approximately 6 mm distal to the bifurcation. Followingretraction of a guidewire and/or straightening sheath, the SymplicitySpyral™ catheter can transform to a spiral/helically-shapedconfiguration that accommodates the inner diameter of a typical renalartery and/or the branches of the renal artery (e.g., about 2-10 mm),placing the electrodes (e.g., 4 electrodes) in contact with the vesselwall. A first (e.g., most distal) lesion can be formed about 5-6 mmdistal to the bifurcation. Following treatment at the first renal arterybranch, the catheter can be withdrawn into the main renal vessel andthen advanced under fluoroscopy into a second renal artery branch andthe treatment procedure can be repeated. Some methods can includetreating two branch vessels at the proximal trunk segment of the branchvessel. Other methods can include treating greater than two or all ofthe primary branch vessels branching from the main renal vessel (e.g.,distal to a primary bifurcation). As described above, these methods mayalso include combining neuromodulation of renal nerve tissue surroundingone or more primary branch trunks with neuromodulation of renal nervetissue at additional treatment locations (e.g., locations along the mainrenal vessel, locations at or near the bifurcation, etc.). Other methodscan include advancing a multi-electrode Symplicity Spyral™ catheter to afirst renal artery branch vessel approximately 10 mm distal to thebifurcation, with a first (e.g., most distal) lesion formed about 9-10mm distal to the bifurcation.

Physiological biomarkers, such as systemic catecholamines and/or theirsubsequent degradation products could be measured in either plasma,serum or urine to serve as surrogate markers to measure proceduralefficacy such as described in International Patent Application No.PCT/US2015/047568, filed Aug. 28, 2015, and incorporated herein byreference in its entirety.

It is anticipated that treating a human patient diagnosed withdepression or having an increased risk of developing depression (e.g., apredisposition, having one or more biomarkers suggesting an increasedlikelihood, genetic/epigenetic factors, etc.) or having one or moremeasurable risk factors predictive for the development of depression,with renal neuromodulation, at one or more of the described treatmentlocations, will inhibit sympathetic neural activity in the renal nervein a manner that reduces a central sympathetic drive (e.g., ascorrelated with whole body norepinephrine spillover and/or renalnorepinephrine spillover) by greater than about 20%, about 30%, about40%, about 50% or greater than about 60% in about 1 month, in about 3months, in about 6 months or in about 12 months, or in anotherembodiment, in about 3 months to about 12 months, after renalneuromodulation treatment. Reduction in central sympathetic drive isanticipated to result in a therapeutically beneficial improvement in oneor more measurable physiological parameters corresponding to anincidence of depression, and/or a severity of depression in the patient.

Example 7

Example 7 describes a method for determining human patients who have acalculated risk score for determining a depression status (e.g.,diagnosis) at or above a threshold depression risk score and treatingsuch patients with targeted sympathetic neuromodulation of renal SNSneural fibers innervating the kidney. In this example, human patientshaving a calculated depression risk score meeting or exceeding athreshold depression risk score will be treated with renalneuromodulation to improve the patient's depression risk score and/orlower the patient's depression risk score (e.g., in a manner thatimproves the patient's depression status, reverses the patient'sdepression diagnosis, and/or improves one or more symptoms orcontributing factors associated with depression in the patient).

Patients presenting one or more risk factors or indicators predictivefor or indicative of depression will be assessed for other possible riskfactors and a depression risk score will be calculated. In this example,a patient will fill out a questionnaire or otherwise have an attendingphysician assess risk factors. A depression risk score calculator basedon risk factor data to determine a probability or likelihood ofdepression status (e.g., diagnosis) in an individual is shown in FIG.10. The depression risk score calculator shown in FIG. 10 is derivedfrom data provided in the Major Depression Inventory study to develop amodel of a technique to assess duration and/or frequency ofdepression-associated symptoms and screen the patient for risk factorsand indicators of depression to determine a likelihood and/or severityof depression diagnosis (Bech, P., et al., BMC Psychiatry, 2015,15:190).

Referring to the depression risk score calculator shown in FIG. 10, apatient will be queried and assessed for core depression symptoms (e.g.,low or sad mood, presence of anhedonia, presence of anergia, lack ofself-confidence, feelings of guilt, presence of feelings that life isnot worth living, difficulty concentrating, feelings of restlessnessand/or slowed or subdued energy levels, sleep disturbances, andincreased or decreased appetite). In addition to these ten clinicalmeasures, the patient may also be examined and/or tested by a physicianfor determination of other physiological variables pertaining to the SNSsuch as, for example, heart rate variability, heart rate reactions tostress, whole body MSNA levels (FIG. 10), and systolic blood pressure(e.g., daytime, nocturnal and morning surge) (not shown in FIG. 10). Inthis example, the input to the calculator will yield both apatient-specific depression risk score as well as an indication as towhether RDN treatment is recommended. In this example, the thresholddepression risk score is 30. An indication of RDN recommendation may bebased on whether the patient's depression risk score is at or above thethreshold depression risk score, either alone or in combination with oneor more physician-administered tests assessing SNS activity or systolicblood pressure level.

As illustrated in FIG. 10, a hypothetical patient reports experiencing 2depression inventory symptoms all of the time, 3 depression inventorysymptoms most of the time, 3 depression inventory symptoms slightly morethan half the time, 1 depression inventory symptom slightly less thanhalf the time, and 1 depression inventory symptom some of the time forthe past two weeks. A physician-administered SNS test assessing heartrate variability indicated the patient's SDNN intervals were less thanthe 50 ms threshold, however the patient met threshold levels in abaroreflex sensitivity test, heart rate reactions to stress, and wholebody MSNA levels. The hypothetical patient's depression risk score of 34exceeds the threshold level determination for depression diagnosis andfor receiving RDN treatment with or without the additional SNS tests (orascertaining a systolic blood pressure for the patient). Followingbilateral renal neuromodulation treatment, the hypothetical patient mayhave improvement in one or more measurable risk factors (e.g., heartrate variability, severity or frequency of sleep disturbances, nocturnaland/or morning surge blood pressure, etc.), and/or reported risk factorspertaining to core depression symptoms (e.g., appetite, mood levels,energy levels), that improves the patient's depression risk score, andin some cases, to levels below the threshold depression risk scorelevel(s).

VIII. FURTHER EXAMPLES

1. In a normotensive patient diagnosed with depression, a methodcomprising:

-   -   intravascularly positioning a neuromodulation assembly within a        renal blood vessel of the patient and adjacent to a renal nerve        of the patient; and    -   at least partially inhibiting sympathetic neural activity in the        renal nerve of the patient via the neuromodulation assembly,    -   wherein at least partially inhibiting sympathetic neural        activity results in a therapeutically beneficial improvement in        a measurable parameter associated with the depression of the        patient.

2. The method of example 1 wherein at least partially inhibitingsympathetic neural activity in the patient in a manner that results in atherapeutically beneficial improvement in a measurable parameterassociated with depression comprises improving a sleep pattern and/or asleep quality of the patient.

3. The method of example 1 or example 2 wherein at least partiallyinhibiting sympathetic neural activity in the patient in a manner thatresults in a therapeutically beneficial improvement in a measurableparameter associated with depression comprises reducing a level ofinsomnia in the patient.

4. The method of any one of examples 1-3 wherein reducing sympatheticneural activity in the patient in a manner that results in atherapeutically beneficial improvement in a measurable parameterassociated with depression comprises reducing a morning surge bloodpressure and/or a nocturnal blood pressure in the patient.

5. The method of one of examples 1-4 wherein reducing sympathetic neuralactivity in the patient in a manner that results in a therapeuticallybeneficial improvement in a measurable parameter associated withdepression comprises improving one or more of feelings of sadness,apathy, mood swings, loss of interest or pleasure in activities, guilt,anxiety, insomnia, restless sleep, excess sleepiness, fatigue, excessivehunger, loss of appetite, irritability, excessive crying, lack ofconcentration, slowness in activity and thoughts of suicide in thepatient as measured on a depression scale.

6. The method of any one of examples 1-5 wherein reducing sympatheticneural activity in the patient further comprises improving one or moredepression-related symptoms in the patient as reported on a depressioninventory scale.

7. The method of example 6 wherein improving one or moredepression-related symptoms in the patient includes reducing a level ofdepression-related symptoms and/or a number of depression-relatedsymptoms.

8. The method of example 6 or example 7 wherein improving one or moredepression-related symptoms in the patient includes reducing a level ofdepression-related symptoms in the patient by at least about 5%, atleast about 10%, at least about 20% or at least about 40%.

9. The method of example 6 or example 7 wherein improving one or moredepression-related symptoms in the patient includes reducing a number ofdepression-related symptoms in the patient by at least about 5%, atleast about 10%, at least about 20% or at least about 40% within aboutthree months to about 12 months after at least partially inhibitingsympathetic neural activity in the patient by delivering energy to therenal nerve.

10. The method of any one of examples 1-9 wherein the patient is female.

11. The method of any one of examples 1-10 wherein the patient isbetween the ages of 18 and 45, between the ages of 18 and 30, betweenthe ages of 20 and 40, or between the ages of 20 and 35.

12. The method of any one of examples 1-10 wherein the patient isbetween the ages of 35 and 65, between the ages of 45 and 65, betweenthe ages of 50 and 70, or the patient is at least 35 years old.

13. The method of any one of examples 1-12 wherein at least partiallyinhibiting sympathetic neural activity in the patient further comprisesreducing an incidence of stroke or cardiovascular disease in thepatient.

14. The method of any one of examples 1-12 wherein the patient has ahistory of cardiovascular disease or stroke, and wherein at leastpartially inhibiting sympathetic neural activity in the patient furthercomprises reducing an incidence of a future cardiovascular event orstroke.

15. The method of example 1 wherein at least partially inhibitingsympathetic neural activity in the patient in a manner that results in atherapeutically beneficial improvement in a measurable parameterassociated with depression comprises improving a patient's depressionrisk score on a depression screening tool.

16. The method of any one of examples 1-15 wherein at least partiallyinhibiting sympathetic neural activity in the patient in a manner thatresults in a therapeutically beneficial improvement in a measurableparameter associated with depression includes one or more of:

-   -   increasing a heart rate variability of the patient;    -   increasing baroreceptor sensitivity in the patient;    -   reducing a morning surge blood pressure in the patient;    -   reducing a plasma cortisol level in the patient;    -   reducing a level of glucocorticoid resistance in the patient;        and    -   reducing a level of an inflammatory biomarker in the patient.

17. The method of example 16 wherein the inflammatory biomarker is atleast one of interleukin-6, interleukin-1β, interleukin-2, tumornecrosis factor-alpha, and C-reactive protein.

18. The method of any one of examples 1-17 wherein reducing sympatheticneural activity in the renal nerve further reduces muscle sympatheticnerve activity (MSNA) in the patient.

19. The method of any one of examples 1-18 wherein reducing sympatheticneural activity in the renal nerve further reduces whole bodynorepinephrine spillover in the patient.

20. The method of example 19 wherein the whole body norepinephrinespillover is reduced by at least about 20% in about one month afterreducing sympathetic neural activity in the renal nerve.

21. The method of example 19 wherein the whole body norepinephrinespillover is reduced by greater than about 40% in about three months toabout 12 months after reducing sympathetic neural activity in the renalnerve.

22. The method of any one of examples 1-21 wherein the patient iscurrently administered one or more pharmaceutical drugs for thedepression, and wherein at least partially inhibiting sympathetic neuralactivity in the patient in a manner that results in a therapeuticallybeneficial improvement in a measurable parameter associated withdepression comprises reducing at least one of a number of or a measureddosage of pharmaceutical drugs administered to the patient for thedepression.

23. The method of example 22 wherein the pharmaceutical drugs includeone or more of an antidepressant, an anti-anxiety drug, ananti-psychotic drug, an insomnia drug or an anti-inflammatory drug.

24. In a human patient, a method of reducing a risk of the patientdeveloping depression, the method comprising:

-   -   intravascularly positioning a catheter carrying a        neuromodulation assembly adjacent to a renal sympathetic nerve        of the patient;    -   delivering energy to the renal sympathetic nerve via the        neuromodulation assembly to attenuate neural traffic along the        renal sympathetic nerve; and    -   removing the catheter and neuromodulation assembly from the        patient after treatment, wherein attenuating neural traffic        along the renal sympathetic nerve reduces a risk of the patient        developing depression.

25. The method of example 24 wherein a risk of developing depression iscalculated using a depression screening tool, and wherein apost-neuromodulation depression risk score, as calculated by thedepression screening tool, for the development of depression for thepatient is lower than an initial depression risk score.

26. The method of example 24 or example 25 wherein attenuating neuraltraffic along the renal sympathetic nerve further results in one or moreof:

-   -   increasing heart rate variability in the patient;    -   increasing baroreceptor sensitivity in the patient;    -   reducing a level of glucocorticoid resistance in the patient;    -   reducing a cortisol level in the patient;    -   reducing a systolic blood pressure of the patient;    -   reducing a morning surge blood pressure in the patient;    -   reducing a nocturnal blood pressure in the patient;    -   reducing muscle sympathetic nerve activity (MSNA) in the        patient;    -   reducing a plasma or urine norepinephrine level in the patient;        and    -   reducing a level of an inflammatory biomarker in the patient.

27. The method of example 26 wherein the inflammatory biomarker is atleast one of interleukin-6, interleukin-1β, interleukin-2, tumornecrosis factor-alpha, and C-reactive protein.

28. The method of any one of examples 24-27 wherein the patient has apersonal or family history of depression, and wherein attenuating neuraltraffic along the renal sympathetic nerve reduces an incidence of afuture depressive episode in the patient.

29. The method of any one of examples 24-28 wherein the patient iscurrently experiencing an adverse life circumstance and is diagnosedwith one or more of low heart rate variability, elevated plasma or urinecatecholamine levels, elevated systolic blood pressure, elevated morningsurge in blood pressure, non-dipping nocturnal blood pressure, lowneuropeptide Y level, elevated plasma cortisol level, glucocorticoidresistance, elevated cortisol awakening rise (CAR), reduced baroreceptorsensitivity, and elevated level of an inflammatory biomarker.

30. The method of any one of examples 24-29 wherein the patient has apolymorphism in at least one of the genes encoding for FK506-bindingprotein 5 (FKBP5 gene), glucocorticoid receptor (NR3C1 gene), serotonintransporter (SLC6A4 gene), cortisol releasing hormone receptor-1 (CRHR1gene), interleukin-1β, tumor necrosis factor (TNF)-alpha, angiotensinconverting enzyme (ACE), and angiotensin receptor (AT₁R) that provide anincreased likelihood of developing depression.

31. The method of any one of examples 24-30 wherein the patient isdiagnosed with cardiovascular disease.

32. The method of any one of examples 24-31 wherein the patient has ahistory of stroke.

33. The method of any of examples 24-32 wherein the patient has one ormore depression risk factors selected from the group consisting ofincreased substance usage, hypertension, elevated norepinephrine wholebody spillover, exposure to multiple traumatic events, female, widowedor divorced marital status, and adverse childhood experience.

34. The method of any one of examples 24-33 wherein attenuating neuraltraffic along the renal sympathetic nerve comprises at least partiallyablating the renal sympathetic nerve.

35. The method of any one of examples 24-33 wherein attenuating neuraltraffic along the renal sympathetic nerve comprises at least partiallydisrupting communication along the renal sympathetic nerve.

36. The method of any one of examples 24-33 wherein attenuating neuraltraffic along the renal sympathetic nerve comprises irreversiblydisrupting communication along the renal sympathetic nerve.

37. The method of any one of examples 24-33 wherein attenuating neuraltraffic along the renal sympathetic nerve comprises delivering an energyfield to the renal sympathetic nerve via the neuromodulation assembly.

38. The method of example 37 wherein delivering an energy field to therenal sympathetic nerve comprises delivering at least one of radiofrequency energy, ultrasound energy, high intensity ultrasound energy,laser energy, and microwave energy via the neuromodulation assembly.

39. The method of any one of examples 24-38 wherein the patient isdiagnosed with prehypertension or hypertension, and wherein attenuatingneural traffic along the renal sympathetic nerve further reduces wholebody norepinephrine spillover in the patient in a manner that reducesthe risk of the patient developing depression.

40. A method for improving a patient's risk score corresponding to adepression status of the patient, the method comprising:

-   -   intravascularly positioning a catheter carrying a        neuromodulation assembly within a renal blood vessel and        adjacent to a renal sympathetic nerve in the patient;    -   delivering energy to the renal sympathetic nerve via the        neuromodulation assembly to attenuate neural traffic along the        renal sympathetic nerve; and    -   removing the catheter and neuromodulation assembly from the        patient after treatment, wherein attenuating neural traffic        along the renal sympathetic nerve results in improving the        patient's risk score corresponding to the depression status of        the patient.

41. The method of example 40 wherein improving the patient's risk scorecorresponding to the depression status of the patient includes one ormore of improving depression-related symptoms, improving the patient'sappetite, improving the patient's sleep quality, reducing a level ofsystemic inflammation in the patient, and improving a patient's bodymass index.

42. The method of example 40 or example 41 wherein the patient isdiagnosed with pre-hypertension or hypertension, and wherein improvingthe patient's risk score corresponding to the depression status of thepatient includes reducing the patient's blood pressure.

43. The method of any one of examples 40-42 wherein a patient's riskscore corresponding to the depression status of the patient is reducedby at least about 10%, at least about 15%, at least about 20%, at leastabout 30% or at least about 40%.

44. The method of any one of examples 40-43 wherein the patient's riskscore is calculated using a depression screening tool, and wherein apost-neuromodulation depression risk score, as calculated by thedepression screening tool, is lower than an initial depression riskscore.

45. The method of example 44, wherein the depression screening toolincludes a Visual Analogue Scale (VAS) for assessing depressionseverity.

46. A method for improving a depression risk score for a human patientdiagnosed with depression, the method comprising performing a renalneuromodulation procedure in the patient diagnosed with depression,wherein a post-neuromodulation risk score is lower than an initial riskscore of the patient diagnosed with depression.

47. The method of example 46 wherein the post-neuromodulation risk scoreis lower than the initial risk score by about 5%, about 10%, about 20%or about 30%.

48. The method of example 46 or example 47 wherein the initial riskscore indicates the patient is at risk of having major depression if theinitial risk score is greater than a threshold risk score.

49. The method of any one of examples 46-48 wherein the initial riskscore and the post-neuromodulation risk score are determined using adepression screening tool for determining a severity of depression ofthe patient.

50. The method of any one of examples 46-49 wherein the initial riskscore and the post-neuromodulation risk score are based upon one or morefactors comprising a psychological evaluation, type and/or severity ofdepression-related symptoms, type and/or duration of adverse lifecircumstance experienced by the patient, number of instances of traumaexposure, and sleep disturbances.

51. A method for managing depression in a human patient, the methodcomprising:

-   -   transluminally positioning an energy delivery element of a        catheter within a renal blood vessel of the patient and adjacent        to renal sympathetic neural fibers in the patient; and    -   at least partially ablating the renal sympathetic neural fibers        via the energy delivery element,    -   wherein at least partially ablating the renal sympathetic neural        fibers results in a therapeutically beneficial improvement in a        measurable parameter associated with depression of the patient.

52. The method of example 51 wherein at least partially ablating therenal sympathetic neural fibers in the patient in a manner that resultsin a therapeutically beneficial improvement in a measurable parameterassociated with depression comprises improving one or both of a sleeppattern or a sleep quality.

53. The method of example 51 or 52 wherein at least partially ablatingthe renal sympathetic neural fibers in the patient in a manner thatresults in a therapeutically beneficial improvement in a measurableparameter associated with depression comprises at least one of reducinga nocturnal blood pressure and reducing a morning surge in bloodpressure in the patient.

54. The method of any one of examples 51-53 wherein at least partiallyablating the renal sympathetic neural fibers in the patient in a mannerthat results in a therapeutically beneficial improvement in a measurableparameter associated with depression comprises improving one or moredepression-related symptoms in the patient.

55. The method of any one of examples 51-54 wherein at least partiallyablating the renal sympathetic neural fibers further results in reducingan incidence of one or more of hypertension, cardiovascular disease,obesity, diabetes, insulin resistance, systemic inflammation, stroke anddementia in the patient.

56. The method of any one of examples 51-55 wherein at least partiallyablating the renal sympathetic neural fibers further results in atherapeutically beneficial improvement in a measurable physiologicalparameter associated with a comorbid condition in the patient.

57. The method of example 56 wherein the comorbid condition is one ormore of cardiovascular disease, hypertension, obesity, metabolicdisorder, systemic inflammation and dementia.

58. The method of any one of examples 51-57, further comprisingadministering one or more pharmaceutical drugs to the patient, whereinthe pharmaceutical drugs are selected from the group consisting ofantidepressants, anti-anxiety drugs, anti-hypertension drugs andanti-inflammatory drugs.

59. The method of any one of examples 51-58 wherein at least partiallyablating the renal sympathetic neural fibers of the patient via theenergy delivery element comprises delivering a thermal electric field tothe sympathetic neural fibers via at least one electrode.

60. A method for treating a patient that can answer affirmatively, ifasked, to at least five of the following statements:

-   -   in the past two weeks and at least most of the time—        -   a) you have felt low in spirits or sad,        -   b) you have lost interest in your daily activities,        -   c) you have felt lacking in energy and strength,        -   d) you have felt less self-confident,        -   e) you have had a bad conscious or feelings of guilt,        -   f) you have felt that life wasn't worth living,        -   g) you have had difficulty in concentrating,        -   h) you have felt very restless,        -   i) you have felt subdued or slowed down,        -   j) you have had trouble sleeping at night,        -   k) you have suffered from reduced appetite,        -   l) you have suffered from increased appetite,            the method comprising:    -   intravascularly positioning a neuromodulation assembly within a        renal blood vessel of the patient and adjacent to a renal nerve        of the patient; and    -   at least partially inhibiting sympathetic neural activity in the        renal nerve of the patient via the neuromodulation assembly,    -   wherein at least partially inhibiting sympathetic neural        activity results in a therapeutically beneficial improvement in        the patient's response to one or more of statements a-l.

IX. CONCLUSION

The above detailed descriptions of embodiments of the technology andmethodology are not intended to be exhaustive or to limit the technologyto the precise forms disclosed above. Although specific embodiments of,and examples for, the technology are described above for illustrativepurposes, various equivalent modifications are possible within the scopeof the technology, as those skilled in the relevant art will recognize.For example, while steps are presented in a given order, alternativeembodiments may perform steps in a different order. The variousembodiments described herein may also be combined to provide furtherembodiments. All references cited herein are incorporated by referenceas if fully set forth herein.

From the foregoing, it will be appreciated that specific embodiments ofthe technology have been described herein for purposes of illustration,but well-known structures and functions have not been shown or describedin detail to avoid unnecessarily obscuring the description of theembodiments of the technology. Where the context permits, singular orplural terms may also include the plural or singular term, respectively.

Moreover, unless the word “or” is expressly limited to mean only asingle item exclusive from the other items in reference to a list of twoor more items, then the use of “or” in such a list is to be interpretedas including (a) any single item in the list, (b) all of the items inthe list, or (c) any combination of the items in the list. Additionally,the term “comprising” is used throughout to mean including at least therecited feature(s) such that any greater number of the same featureand/or additional types of other features are not precluded. It willalso be appreciated that specific embodiments have been described hereinfor purposes of illustration, but that various modifications may be madewithout deviating from the technology. Further, while advantagesassociated with certain embodiments of the technology have beendescribed in the context of those embodiments, other embodiments mayalso exhibit such advantages, and not all embodiments need necessarilyexhibit such advantages to fall within the scope of the technology.Accordingly, the disclosure and associated technology can encompassother embodiments not expressly shown or described herein.

1.-20. (canceled)
 21. A method of reducing a risk of a patientdeveloping depression, the method comprising: intravascularlypositioning a catheter carrying a neuromodulation assembly adjacent to arenal sympathetic nerve of the patient; delivering energy to the renalsympathetic nerve via the neuromodulation assembly to attenuate neuraltraffic along the renal sympathetic nerve; and removing the catheter andneuromodulation assembly from the patient after treatment, whereinattenuating neural traffic along the renal sympathetic nerve lowers arisk score associated with the risk of the patient developingdepression.
 22. The method of claim 21, further comprising: determiningan initial depression risk score for the patient prior to energydelivery; determining a post-neuromodulation depression risk score afterthe energy delivery; comparing the post-neuromodulation depression riskscore with the initial depression risk score; and determining whetherneuromodulation sufficiently modulated the renal sympathetic nerve basedon the comparison.
 23. The method of claim 22, wherein determining thepost-neuromodulation depression risk score after energy delivery occursafter the removal of the neuromodulation assembly from the patient. 24.The method of claim 22, wherein determining the post-neuromodulationrisk score includes using a depression screening tool to calculate thepost-neuromodulation risk score.
 25. The method of claim 21, wherein thepatient has one or more depression risk factors selected from the groupconsisting of increased substance usage, hypertension, elevatednorepinephrine whole body spillover, exposure to multiple traumaticevents, female, widowed or divorced marital status, and adversechildhood experience.
 26. The method of claim 21, wherein the patienthas a personal or family history of depression, and wherein attenuatingneural traffic along the renal sympathetic nerve reduces an incidence ofa future depressive episode in the patient.
 27. The method of claim 21,wherein the patient is currently experiencing an adverse lifecircumstance and is diagnosed with one or more of low heart ratevariability, elevated plasma or urine catecholamine levels, elevatedsystolic blood pressure, elevated morning surge in blood pressure,non-dipping nocturnal blood pressure, low neuropeptide Y level, elevatedplasma cortisol level, glucocorticoid resistance, elevated cortisolawakening rise (CAR), reduced baroreceptor sensitivity, and elevatedlevel of an inflammatory biomarker.
 28. The method of claim 21, whereinthe patient has a polymorphism in at least one of the genes encoding forFK506-binding protein 5 (FKBP5 gene), glucocorticoid receptor (NR3C1gene), serotonin transporter (SLC6A4 gene), cortisol releasing hormonereceptor-1 (CRHR1 gene), interleukin-1β, tumor necrosis factor(TNF)-alpha, angiotensin converting enzyme (ACE), and angiotensinreceptor (AT₁R) that provide an increased likelihood of developingdepression.
 29. A method for improving a risk score that corresponds toa depression status of a patient, the method comprising: intravascularlypositioning a catheter carrying a neuromodulation assembly within arenal blood vessel and adjacent to a renal sympathetic nerve in thepatient; delivering energy to the renal sympathetic nerve via theneuromodulation assembly to attenuate neural traffic along the renalsympathetic nerve; and removing the catheter and neuromodulationassembly from the patient after treatment, wherein attenuating neuraltraffic along the renal sympathetic nerve results in improving the riskscore corresponding to the depression status of the patient.
 30. Themethod of claim 29, wherein the risk score is calculated using adepression screening tool, and wherein a post-neuromodulation depressionrisk score, as calculated by the depression screening tool, is lowerthan a baseline depression risk score.
 31. The method of claim 30,wherein the baseline depression risk score and the post neuromodulationdepression risk score are based upon one or more factors comprising apsychological evaluation, type and/or severity of depression-relatedsymptoms, type and/or duration of adverse life circumstance experiencedby the patient, number of instances of trauma exposure, and sleepdisturbances.
 32. The method of claim 29, wherein improving the riskscore corresponding to the depression status of the patient includes oneor more of improving depression-related symptoms, improving an appetiteof the patient, improving a sleep quality of the patient, reducing alevel of systemic inflammation in the patient, and improving a body massindex of the patient.
 33. The method of claim 29, further comprising:determining an initial depression risk score for the patient prior toenergy delivery; determining a post-neuromodulation depression riskscore after the energy delivery; comparing the post-neuromodulationdepression risk score with the initial depression risk score; anddetermining whether neuromodulation sufficiently modulated the renalsympathetic nerve based on the comparison.
 34. The method of claim 29,wherein determining the post-neuromodulation depression risk score afterenergy delivery occurs after the removal of the catheter and theneuromodulation assembly from the patient.
 35. A method of reducing arisk of a patient developing depression, the method comprising:determining an initial depression risk score for the patient prior toenergy delivery; intravascularly positioning a catheter carrying aneuromodulation assembly adjacent to a renal sympathetic nerve of thepatient; delivering energy to the renal sympathetic nerve via theneuromodulation assembly to attenuate neural traffic along the renalsympathetic nerve; determining a post-neuromodulation depression riskscore after the energy delivery; and comparing the initial depressionrisk score with the post-neuromodulation risk score.
 36. The method ofclaim 35, further comprising: determining whether neuromodulationsufficiently modulated the renal sympathetic nerve based on thecomparison.
 37. The method of claim 35, further comprising: comparingthe initial depression risk score to a threshold risk score; anddetermining that the initial depression risk score is greater than thethreshold risk score prior to the delivery of energy.
 38. The method ofclaim 37, wherein determining that the initial depression risk score isgreater than the threshold risk score indicates that the patient is asuitable candidate that has an identifiable depression risk factor. 39.The method of claim 35, further comprising: removing the neuromodulationassembly from the patient, wherein determining the post-neuromodulationdepression risk score after the energy delivery occurs after removal ofthe neuromodulation assembly from the patient.
 40. The method of claim35, wherein the post-neuromodulation depression risk score is calculatedusing a depressing screening tool.